Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[OH:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([O:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:7]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: OCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Clc1cc(OCCN2CCOCC2)ncn1
Temperature: 25 °C
Reaction time: 15 h
Yield: 321.4 %

Procedure:
A mixture of 4,6-dichloropyrimidine (1.0 g, 6.7 mmol), N-(2-hydroxyethyl)morpholine (0.79 g, 0.60 mmol), and potassium carbonate (2.8 g, 20 mmol) in acetonitrile (5 mL) was stirred at room temperature for 15 h. The solvent was removed in vacuo and the residue was purified on a silica gel column using a gradient dichloromethane/methanol, (100:1 to 2:1), as the eluent to give 0.47 g (32% yield) of the yellow title compound: 1H NMR (CDCl3, 400 MHz) δ 8.48 (s, 1H), 6.72 (s, 1H), 4.45 (t, J=6 Hz, 2H), 3.62 (m, 4H), 2.46 (m, 4H) 2.69 (t, J=6 Hz, 2H), 13C NMR (CDCl3, 100 MHz) δ 169.9, 160.5, 157.9, 107.8, 66.7, 64.4; MS (ESP) m/z 244 (M++1).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH:4]([CH2:7][CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])O)[CH2:3]1.N.[Li]>>[CH3:16][C:11]1[CH2:12][CH:13]=[CH:14][CH2:15][C:10]=1[CH2:8][CH2:7][CH:4]1[CH2:5][CH2:6][N:2]([CH3:1])[CH2:3]1
Reactant: Cc1ccccc1C(O)CC1CCN(C)C1
Agent: N
Agent: [Li]
Product: CC1=C(CCC2CCN(C)C2)CC=CC1

Procedure:
A sample of 1-methyl-α-(2-methylphenyl)-3-pyrrolidine-ethanol (23 α, 0.105 moles) is subjected to Birch reduction in 500 ml liquid ammonia with 7 g (1 mole) of lithium to give a quantitative yield of 3-(3,6-dihydro-2-methylphenethyl)-N-methylpyrrolidine.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](C)(C)[O:22][SiH2]C(C)(C)C)=[C:17]([O:30][CH3:31])[CH:16]=2)=[CH:9][C:8]=1[F:32])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[F:32][C:8]1[CH:9]=[C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][OH:22])=[C:17]([O:30][CH3:31])[CH:16]=2)[CH:11]=[CH:12][C:7]=1[CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:33]
Reactant: CCOC(=O)CCc1ccc(OCc2ccc(C(C)(C)O[SiH2]C(C)(C)C)c(OC)c2)cc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCOC(=O)CCc1ccc(OCc2ccc(CO)c(OC)c2)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 131.4 %

Procedure:
To a solution of 3-{4-[4-(tert-butyl-dimethyl-silanyloxymethyl)-3-methoxy-benzyloxy]-2-fluoro-phenyl}-propionic acid ethyl ester (1 g, 2.1 mmol) in THF (15 mL) is added tetra-n-butylammoniumfluoride (1 M in THF, 3.15 mL, 3.15 mmol) at 0° C. and the reaction mixture is stirred for 2 hour at 25° C. The reaction mixture is quenched with water and concentrated. The residue is diluted with EtOAc, washed with water (15 mL) and brine (15 mL), dried over sodium sulfate, filtered, and concentrated to give the title compound (1.0 g, crude). The crude product is used without further purification.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH2:15])[N:13]=[CH:14][C:9]=3[C:8]3[CH:16]=[CH:17][N:18]=[CH:19][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:21]1[N:26]=[CH:25][C:24]([CH2:27][N:28]2[CH2:33][CH2:32][NH:31][C:30](=[O:34])[CH2:29]2)=[CH:23][CH:22]=1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:21]4[N:26]=[CH:25][C:24]([CH2:27][N:28]5[CH2:33][CH2:32][NH:31][C:30](=[O:34])[CH2:29]5)=[CH:23][CH:22]=4)[N:13]=[CH:14][C:9]=3[C:8]3[CH:16]=[CH:17][N:18]=[CH:19][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Nc1ncc2c3ccncc3n(C3CCCC3)c2n1
Reactant: O=C1CN(Cc2ccc(Cl)nc2)CCN1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: O=C1CN(Cc2ccc(Nc3ncc4c5ccncc5n(C5CCCC5)c4n3)nc2)CCN1
Yield: 61.6 %

Procedure:
In a 10 mL microwave reaction vessel were placed compound 4 (93 mg, 367 μmol), compound 356 (83 mg, 367 μmol), tris(dibenzylideneacetone)dipalladium (0) (17 mg, 18 μmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (27 mg, 46 μmol), and cesium carbonate (359 mg, 1101 μmol) followed by 1,4-dioxane (3 mL). The vessel was purged with N2 for 5 min, then capped and subjected to microwave irradiation for 4 h at 120° C. The crude mixture was taken up in 4% methanol/DCM and subjected to combi-flash column chromatography (methanol/DCM) followed by preparative reverse phase HPLC (acetonitrile/water containing 0.1% TFA each, 40 min from 10 to 40%). Lyophilization provided compound 355 (100 mg) as an off-white solid (TFA salt). 1H NMR (500 MHz, CD3OD) δ ppm 9.67 (1 H, s), 9.34 (1 H, s), 8.69 (1 H, d), 8.66 (1 H, d), 8.48 (1 H, d, J=1.7 Hz), 8.24 (1 H, dd, J=8.8, 2.2 Hz), 8.04 (1 H, d, J=8.6 Hz), 5.48 (1 H, quin, J=8.7 Hz), 4.03 (2 H, s), 3.40-3.49 (4 H, m), 3.09 (2 H, t, J=5.3 Hz), 2.48-2.60 (2 H, m), 2.14-2.32 (4 H, m), 1.85-1.98 (2 H, m). LCMS-ESI (POS), M/Z, M+1: Found 443.2.
Reaction SMILES: [CH:1]1([N:7]([CH2:32][CH2:33][NH:34][CH2:35][CH2:36][C:37]2[C:45]3[S:44][C:43](=[O:46])[NH:42][C:41]=3[C:40]([OH:47])=[CH:39][CH:38]=2)[C:8](=[O:31])[CH2:9][CH2:10][N:11]([CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=2)C(=O)OCC2C=CC=CC=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[BrH:48].COC(C)(C)C>C(O)(=O)C>[BrH:48].[BrH:48].[CH:1]1([N:7]([CH2:32][CH2:33][NH:34][CH2:35][CH2:36][C:37]2[C:45]3[S:44][C:43](=[O:46])[NH:42][C:41]=3[C:40]([OH:47])=[CH:39][CH:38]=2)[C:8](=[O:31])[CH2:9][CH2:10][NH:11][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(OCc1ccccc1)N(CCC(=O)N(CCNCCc1ccc(O)c2[nH]c(=O)sc12)C1CCCCC1)CCc1cccc(F)c1
Agent: Br
Solvent: CC(=O)O
Solvent: COC(C)(C)C
Product: O=C(CCNCCc1cccc(F)c1)N(CCNCCc1ccc(O)c2[nH]c(=O)sc12)C1CCCCC1
Reaction time: 1.33 h

Procedure:
To a solution of the product from step ii) (1 g) in acetic acid (3 mL) stirred at room temperature was added hydrobromic acid in acetic acid (33%, 3 mL). The mixture was stirred for 80 min and then tert-butyl methyl ether (8 mL) was added. The mixture was stirred for 5 min and then filtered, washing with t-butyl methyl ether (8 mL). Purification by recrystallisation from hot ethanol (20 mL) gave the title compound (0.82 g) as a solid.
Reaction SMILES: Cl.[CH2:2]([C@@H:4]1[CH2:8][NH:7][CH2:6][C@H:5]1[C:9]1[NH:10][C:11](=[O:24])[C:12]2[CH:17]=[N:16][N:15]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:13]=2[N:14]=1)[CH3:3].C(=O)([O-])[O-].[K+].[K+].Br.Br[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1>C(#N)C>[CH2:2]([C@@H:4]1[CH2:8][N:7]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=2)[CH2:6][C@H:5]1[C:9]1[NH:10][C:11](=[O:24])[C:12]2[CH:17]=[N:16][N:15]([CH:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[C:13]=2[N:14]=1)[CH3:3]
Reactant: CC[C@@H]1CNC[C@H]1c1nc2c(cnn2C2CCOCC2)c(=O)[nH]1
Reactant: BrCc1ccccn1
Agent: Br
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: CC[C@@H]1CN(Cc2ccccn2)C[C@H]1c1nc2c(cnn2C2CCOCC2)c(=O)[nH]1

Procedure:
To a solution of 6-[(3S,4S)-4-ethylpyrrolidin-3-yl]-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one hydrogen chloride (51 mg) in acetonitrile (1 mL) was added potassium carbonate (88 mg) and 2-(bromomethyl)pyridine hydrogen bromide (40 mg) and the reaction mixture was heated at reflux for 72 h in a sealed vial. The reaction mixture was concentrated onto silica and purified via CombiFlash flash chromatography to provide the title compound. 400 MHz 1H NMR (CDCl3) δ 11.50 (brs, 1H), 8.63 (dd, J=1.7, 0.83, Hz, 1H), 8.02 (s, 1H), 7.70-7.67 (m, 1H), 7.40 (d, J=7.9 Hz, 1H), 7.20-7.16 (m, 1H), 4.79-4.77 (m, 1H), 4.12-4.02 (m, 3H), 3.75-3.72 (m, 1H), 3.61-3.53 (m, 2H), 3.39 (t, J=7.9 Hz, 1H), 3.07 (d, J=9.9 Hz, 1H), 2.92-2.90 (m, 1H), 2.37-2.12 (m, 4H), 1.91-1.83 (m, 2H), 1.65-1.60 (m, 1H), 1.54-1.49 (m, 1H), 0.94 (t, J=7.1 Hz, 3H). MS: (M+H m/z 409.1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=O)=[N:6][CH:7]=1.C(O)(=O)[CH2:11][C:12]([OH:14])=[O:13].N1CCCCC1>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[CH:11][C:12]([OH:14])=[O:13])=[N:6][CH:7]=1
Reactant: O=Cc1ccc(Br)cn1
Reactant: O=C(O)CC(=O)O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)C=Cc1ccc(Br)cn1
Temperature: 100 °C
Reaction time: 1 h
Yield: 53.8 %

Procedure:
5-Bromo-pyridin-2-carbaldehyde (2.0 g, 10.6 mmol), malonic acid (2.5 g, 24.2 mmol), and piperidine (0.9 mL, 9.0 mmol) were added to pyridine (6.5 mL). The reaction mixture was stirred at 100° C. for 1 hour and then concentrated under reduced pressure. Distilled water was added to the reaction mixture, which was then filtered. The resulting solid was dried under reduced pressure to give 1.3 g of the titled compound as a brown solid.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:12][CH2:11][CH:10](O)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CS(Cl)(=O)=O.[C:19]1([CH:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:26]#[N:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Na]>C(N(CC)CC)C>[C:28]1([C:25]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)([CH:10]2[CH2:11][CH2:12][N:8]([CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:9]2)[C:26]#[N:27])[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: N#CC(c1ccccc1)c1ccccc1
Reactant: OC1CCN(Cc2ccccc2)C1
Agent: CS(=O)(=O)Cl
Agent: [Na]
Solvent: CCN(CC)CC
Product: N#CC(c1ccccc1)(c1ccccc1)C1CCN(Cc2ccccc2)C1

Procedure:
The title compound was prepared from 1-(phenylmethyl)-3-pyrrolidinol, methanesulfonylchloride, triethylamine and sodium diphenylacetonitrile by the procedure of U.S. Pat. No. 3,192,210, b.p. 215-218/0.01 mm.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH2:11][CH2:12][C:13]1[S:14][CH:15]=[CH:16][CH:17]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:11][CH2:12][C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: NCc1cccs1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1cccs1)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 97.6 %

Procedure:
A solution of 4-chlorobenzoyl chloride (0.114 mol) in 50 mL dry CH2Cl2 was added over 30 min to a stirred solution of 2-aminomethyl-thiophene (0.137 mol) and iPr2NEt (0.25 mol) in CH2Cl2 (200 mL) at 0° C. A white solid was formed and the reaction was allowed to warm to room temperature over 1 h. The mixture was diluted with 200 mL of CH2Cl2, washed twice with HCl aq. (0.1N) and dried over MgSO4. Evaporation of the solvents afforded 28 g (98%) of the title benzamide (1a) as a white solid: m.p. 153-54° C., 1H NMR (CDCl3) δ 7.9 (d, J=8.67 Hz, 2H), 7.58 (d, J=8.67 Hz, 2H), 7.44 (dd, J=3.77, 1.13 Hz, 1H), 7.22 (d, J==5.27 Hz, 1H), 7.16 (dd, J=3.39, 5.27 Hz, 1H), 6.62 (br d, 1H), 4.98 (d, J=5.65 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([O:9]C)[C:3]=1[B:11]([OH:13])[OH:12].B(Br)(Br)Br>>[F:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([OH:9])[C:3]=1[B:11]([OH:12])[OH:13]
Reactant: COc1ccc(C)c(F)c1B(O)O
Agent: BrB(Br)Br
Product: Cc1ccc(O)c(B(O)O)c1F
Temperature: 0 °C
Reaction time: 2 h
Yield: 100.1 %

Procedure:
A mixture of (2-fluoro-6-methoxy-3-methylphenyl)boronic acid (200 mg, 1.087 mmol) was cooled to 0° C. and BBr3 (0.308 mL, 3.26 mmol) was added. The mixture was then stirred at rt for 2 h. It was then poured into ice and extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated to obtain 185 mg (95%) of the desired product as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.57 (s, 1H), 7.25-7.15 (m, 1H), 6.71-6.61 (m, 1H), 5.76-5.53 (m, 2H), 2.20 (d, J=2.0 Hz, 3H). LCMS (M+23)=193.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=2)=[CH:14][CH:13]=1
Reactant: N#CCc1ccc(Br)cc1
Reactant: OB(O)c1ccc(F)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: N#CCc1ccc(-c2ccc(F)cc2)cc1

Procedure:
The method described in Example 3 (step 3.2.) is used. Starting from 4.12 g (32.48 mmol) of (4-bromophenyl)acetonitrile, 5 g (35.73 mmol) of 4-fluorophenylboronic acid, 32.48 ml (64.96 mmol) of aqueous sodium carbonate (2M) solution and 1.24 g (1.07 mmol) of palladium tetrakis(triphenylphosphine), 3.3 g of pure product are obtained in the form of a white solid, following chromatography on silica gel, eluting with a 15/85 mixture of ethyl acetate and cyclohexane.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.[OH:9]O.[OH-].[Na+]>C(O)(=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N+:3]=1[O-:9]
Reactant: OO
Reactant: Cc1ccc(C)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Cc1ccc(C)[n+]([O-])c1

Procedure:
20 g of 2,5-dimethylpyridine were dissolved in 100 ml of glacial acetic acid and then stirred for 5 hours at 80° to 90° C. with 35 ml of 30% H2O2. The excess glacial acetic acid was rotated out and the solution adjusted to pH 8 with 20% NaOH. After extracting with petrol and discarding the organic phase, the solution was extracted with dichloromethane and the organic phase rotated in. 12 g of 2,5-dimethylpyridine-N-oxide were obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[CH2:11][CH2:10][C@@H:9]([N:12]([CH3:14])[CH3:13])[CH2:8]2)=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=1.[I:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[CH3:31])[C:25](Cl)=[O:26].IC1C=C(C=CC=1C)C(O)=O.O=S(Cl)Cl.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH3:13][N:12]([CH3:14])[C@@H:9]1[CH2:10][CH2:11][N:7]([CH2:6][C:5]2[CH:15]=[CH:16][C:2]([NH:1][C:25](=[O:26])[C:24]3[CH:28]=[CH:29][C:30]([CH3:31])=[C:22]([I:21])[CH:23]=3)=[CH:3][C:4]=2[C:17]([F:20])([F:18])[F:19])[CH2:8]1
Reactant: Cc1ccc(C(=O)Cl)cc1I
Reactant: CN(C)[C@@H]1CCN(Cc2ccc(N)cc2C(F)(F)F)C1
Agent: Cc1ccc(C(=O)O)cc1I
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)Nc2ccc(CN3CC[C@@H](N(C)C)C3)c(C(F)(F)F)c2)cc1I
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a cooled (0° C.) solution of (R)-1-(4-amino-2-(trifluoromethyl)benzyl)-N,N-dimethylpyrrolidin-3-amine (3.79 mmol) in 14 mL DCM, under an atmosphere of N2, was added 3-Iodo-4-methylbenzoyl chloride (1.17 g, 4.17 mmol; CAS#52107-98-9, prepared from the reaction of 3-iodo-4-methylbenzoic acid and SOCl2) followed by dropwise addition of N,N-diisopropylethylamine (2.64 mL, 15.2 mmol). After stirring to ambient temperature over 1.5 h, the reaction mixture was concentrated and the crude product was purified by silica gel chromatography (eluted with 0-8% MeOH/DCM; MeOH was pre-saturated with ammonia gas), to provide 0.71 g of product as a thick yellow oil.
Reaction SMILES: [CH2:1]([C:3]1([CH2:13][C:14]([CH:20]=[N:21][C:22]2[CH:31]=[CH:30][CH:29]=[C:28]3[C:23]=2[CH:24]=[CH:25][N:26]=[CH:27]3)([OH:19])[C:15]([F:18])([F:17])[F:16])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4]1)[CH3:2].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C>[CH2:1]([C:3]1([CH2:13][C:14]([CH2:20][NH:21][C:22]2[CH:31]=[CH:30][CH:29]=[C:28]3[C:23]=2[CH:24]=[CH:25][N:26]=[CH:27]3)([OH:19])[C:15]([F:16])([F:17])[F:18])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4]1)[CH3:2]
Reactant: CCC1(CC(O)(C=Nc2cccc3cnccc23)C(F)(F)F)CCCc2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCC1(CC(O)(CNc2cccc3cnccc23)C(F)(F)F)CCCc2ccccc21
Reaction time: 4 h

Procedure:
To a solution of 3-(1-ethyl-1,2,3,4-tetrahydro-1-naphthalenyl)-1,1,1-trifluoro-2-[(5-isoquinolinylimino) methyl]-2-propanol (Intermediate 18) (185 mg, 0.43 mmol) in glacial acetic acid (5 ml) stirred under nitrogen at room temperature, was added sodium triacetoxyborohydride (276 mg, 1.3 mmol) and the solution was stirred for approximately 4 h. Further sodium triacetoxyborohydride (100 mg, 0.47 mmol) was added and the reaction was stirred for 1 h. The solution was then carefully added to saturated aqueous sodium carbonate and when effervescence had ceased was extracted into ethyl acetate (×2). The combined organic layers were washed successively with saturated aqueous sodium carbonate solution, water and finally brine/water (1:1), passed through a hydrophobic frit and evaporated in vacuo to yield a pale yellow oil. The crude product was purified on a 10 g silica SPE cartridge eluting with a 0-100% dichloromethane in heptane gradient followed by 1% methanol in dichloromethane. This gave, in order of elution, Example 4-D2 (racemic diastereomer 2) (45 mg) and Example 4-D1 (racemic diastereomer 1) (35 mg).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][N:3]=1.[CH3:10][O:11][CH2:12][CH2:13][NH2:14].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Br:1][C:2]1[N:3]=[CH:4][C:5]([CH2:6][NH:14][CH2:13][CH2:12][O:11][CH3:10])=[CH:8][CH:9]=1
Reactant: COCCN
Reactant: O=Cc1ccc(Br)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COCCNCc1ccc(Br)nc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 79 %

Procedure:
To a dark-yellow solution of 6-bromopyridine-3-carbaldehyde 7 (30 g, 161 mmol) in DCM (300 ml) and 2-methoxyethylamine 8 (1.05 eq, 14.72 ml, 169 mmol) in a 1 L round-bottom flask was added acetic acid (1 eq, 9.23 mL, 161 mmol). After 15 min, sodium triacetoxyborohydride (1.05 eq, 35.9 g, 169 mmol) was added over 10 min and the reaction mixture was stirred at r.t. for 30 min. The reaction mixture was then quenched with 10% HCl (200 mL). The two layers were separated and the organic layer was extracted with 10% HCl (2×100 mL). The aqueous layers were combined, basified to pH=9 with 4M NaOH (450 mL), extracted with EA (3×150 mL) and combined organic extracts were washed with brine (150 mL), dried over Na2SO4, filtered and evaporated to afford 9 as brown oil that could be used crude for next step (31.1 g, 127 mmol, 79% yield). MS (m/z): 245.1 (M+1)
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]([OH:21])=[O:20])=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)OCC1.[NH2:22][CH2:23][C@@H:24]([C:26]1[CH:27]=[CH:28][C:29]([OH:37])=[C:30]([NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[CH:31]=1)[OH:25].C(O)(=O)C>CO.[Pd]>[OH:25][C@H:24]([C:26]1[CH:27]=[CH:28][C:29]([OH:37])=[C:30]([NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[CH:31]=1)[CH2:23][NH:22][CH:5]1[CH2:6][CH2:7][N:8]([C:11]2[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:15][CH:16]=2)[CH2:9][CH2:10]1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Reactant: O=C(O)/C=C/c1ccc(N2CCC3(CC2)OCCO3)cc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNC2CCN(c3ccc(CCC(=O)O)cc3)CC2)ccc1O
Reaction time: 24 h
Yield: 94.2 %

Procedure:
A solution of (E)-3-[4-(4-oxo-piperidine-1-yl)-phenyl]-acrylic acid (which was obtained in Example 170) (0.10 g, 0.40 mmol) and N-[5-((1R)-2-Amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methane-sulfonamide (which was obtained in Example 10) (0.12 g, 0.48 mmol) in methanol (15 mL) was treated with acetic acid (0.03 g, 0.5 mmol), and 0.05 g of 10% Pd/C. The mixture was hydrogenated at 25 psi for 24 h, and then filtered through Celite and evaporated. The residue was triturated with ether to give 0.18 g of an off-white solid; m.p. 130-133° C.; 1H NMR (DMSO-d6) δ 1.30-1.46 (m, 2H), 1.84-1.95 (m, 2H), 2.37-2.50 (m, 4H), 2.60-2.78 (m, 4H), 2.92 (s, 3 H), 3.53-3.62 (m, 3H), 4.46-4.55 (m, 1H), 6.85 (d, 2H), 6.92-7.10 (m, 4H), 7.18 (dd, 1H); MS (ES) m/z: 478.3 (MH+).
Reaction SMILES: C([O:4][C@@H:5]([CH3:30])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[N:17]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]([CH3:28])=[N:15][C:14]=2[N:13]([CH3:29])[C:11]1=[O:12])(=O)C.Cl>CO.CCOCC>[CH2:21]([N:17]1[C:18]2[C:19](=[O:20])[N:10]([CH2:9][CH2:8][CH2:7][CH2:6][C@@H:5]([OH:4])[CH3:30])[C:11](=[O:12])[N:13]([CH3:29])[C:14]=2[N:15]=[C:16]1[CH3:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(=O)O[C@@H](C)CCCCn1c(=O)c2c(nc(C)n2Cc2ccccc2)n(C)c1=O
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: Cc1nc2c(c(=O)n(CCCC[C@H](C)O)c(=O)n2C)n1Cc1ccccc1
Reaction time: 12 h

Procedure:
A solution of (S)-1-(5-acetoxyhexyl)-7-benzyl-3,8-dimethylxanthine (350 mg) in methanol (20 ml) was treated with 1 M hydrochloric acid in ether (2.5 ml) and stirred for 12 hours. After evaporation of volatiles under reduced pressure, the residue was dissolved in ethyl acetate (100 ml), washed with saturated aqueous sodium bicarbonate solution (30 ml), dried over magnesium sulfate and concentrated. Yield=270 mg.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[NH2:6].Cl.[O:13]1CCOC[CH2:14]1.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:6]=[C:14]=[O:13])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(N)cc1OC
Reactant: C1COCCO1
Agent: Cl
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Product: COc1ccc(N=C=O)cc1OC
Temperature: 60 °C
Yield: 97 %

Procedure:
A 3 L, three-necked, round-bottomed flask was equipped with a heating/cooling bath, magnetic stirrer and stir bar, condenser, 500 mL addition funnel, thermocouple, nitrogen inlet, heating bath, vacuum distillation apparatus. To a stirred solution of 3,4-dimethoxyaniline (81.9 g, 535 mmol) in xylenes (1400 mL) was added via the addition funnel, a 4 N solution of hydrogen chloride in 1,4-dioxane (295 mL, 1180 mmol) at ambient temperature. This mixture was stirred at ˜25° C. for 30 minutes, before it was heated to reflux under a slow N2 stream. Neat triphosgene (200.0 g, 674 mmol) was added to the refluxing stirred mixture in portions via the addition funnel over 45 minutes. Upon completion of the addition, the batch was refluxed for another hour. After cooling to ˜60° C., the batch was concentrated under reduced pressure to remove most of the solvent. The oily residue was distilled under high vacuum (b.p. 84-88° C. @ 0.92 mmHg) to afford the title compound as an oil (93.0 g, 97%).
Reaction SMILES: [F:1][C:2]1([F:13])[O:6][C:5]2[CH:7]=[CH:8][C:9]([CH:11]=O)=[CH:10][C:4]=2[O:3]1.[CH2:14]([NH2:18])[CH2:15][CH2:16][CH3:17]>C(Cl)Cl>[CH2:14]([N:18]=[CH:11][C:9]1[CH:8]=[CH:7][C:5]2[O:6][C:2]([F:13])([F:1])[O:3][C:4]=2[CH:10]=1)[CH2:15][CH2:16][CH3:17]
Reactant: CCCCN
Reactant: O=Cc1ccc2c(c1)OC(F)(F)O2
Solvent: ClCCl
Product: CCCCN=Cc1ccc2c(c1)OC(F)(F)O2
Reaction time: 20 h

Procedure:
0.10 mol of 2,2-difluoro-5-formyl-1,3-benzodioxole are dissolved in 150 ml of methylene chloride, and 0.12 mol of n-butylamine is added at room temperature, with gentle cooling. The mixture is left to stand at room temperature for 20 hours, without stirring, the solvent is distilled off, together with the water which has separated out, under a slight vacuum, a further 150 ml of methylene chloride are added and are distilled off and the oil which remains is dried under an oil pump vacuum. The butylimino compound can be used in the crude form, for example in Example 2.