Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[C:12]([C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[CH2:20][CH:19]([CH2:24][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:18][CH2:17]2)#[N:13].[H-].[Na+].[C:46]([O:50][C:51]([N:53]1[CH2:57][CH2:56][C@H:55]([O:58][C:59]2[CH:64]=[CH:63][C:62]([C:65](=O)[C:66]([O:68][CH2:69][CH3:70])=[O:67])=[CH:61][CH:60]=2)[CH2:54]1)=[O:52])([CH3:49])([CH3:48])[CH3:47]>O1CCCC1.C(OCC)(=O)C>[C:46]([O:50][C:51]([N:53]1[CH2:57][CH2:56][C@H:55]([O:58][C:59]2[CH:60]=[CH:61][C:62]([C:65](=[CH:24][CH:19]3[CH2:18][CH2:17][C:16]4[C:21](=[CH:22][CH:23]=[C:14]([C:12]#[N:13])[CH:15]=4)[CH2:20]3)[C:66]([O:68][CH2:69][CH3:70])=[O:67])=[CH:63][CH:64]=2)[CH2:54]1)=[O:52])([CH3:49])([CH3:48])[CH3:47]
Reactant: CCOC(=O)C(=O)c1ccc(O[C@H]2CCN(C(=O)OC(C)(C)C)C2)cc1
Reactant: N#Cc1ccc2c(c1)CCC(C[P+](c1ccccc1)(c1ccccc1)c1ccccc1)C2
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C(=CC1CCc2cc(C#N)ccc2C1)c1ccc(O[C@H]2CCN(C(=O)OC(C)(C)C)C2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 65.9 %

Procedure:
9.0 g of (6-cyano-1,2,3,4-tetrahydro-2-naphthyl)methyltriphenylphosphonium p-toluenesulfonate was suspended in 150 ml of tetrahydrofuran, followed by gradual addition of 600 mg of 60% sodium hydride. The thus prepared mixture was refluxed under heating for 20 minutes. After cooling down to room temperature, to the resulting reaction solution was added 10 ml of a tetrahydrofuran solution containing 4.16 g of ethyl 2-[4-[((3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl)oxy]phenyl]-2-oxoacetate. The resulting reaction mixture was stirred for 10 minutes, and then refluxed under heating for 2 hours. After cooling down to room temperature, the reaction product thus obtained was dissolved in ethyl acetate, and washed with water and saturated sodium chloride aqueous solution in that order. After drying the resulting organic layer to distill off the solvent, the thus obtained residue was purified by subjecting it to silica gel column chromatography using a n-hexane/ethyl acetate mixture as an elution solvent, thereby obtaining 3.90 g of ethyl 2-[4-[((3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl)oxy]phenyl]-3-(6-cyano-1,2,3,4-tetrahydro-2-naphthyl)acrylate in a yellow oily form as a mixture of E and Z forms. 2.58 g of the thus obtained E/Z mixture was dissolved in 40 ml of ethanol, and the resulting solution was mixed with 650 mg of palladium oxide.1H2O.barium sulfate, and then subjected to catalytic hydrogenation under normal pressure for 5 hours. After removing the catalyst by filtration and distilling off the solvent, the resulting residue was purified by subjecting it to silica gel column chromatography using a n-hexane/ethyl acetate mixture as an elution solvent. In this way, 1.69 g of the title compound was obtained in a yellow oily form.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([N+:19]([O-])=O)[CH:13]=1.CCO.[Cl-].[NH4+]>[Fe].O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([NH2:19])[CH:13]=1
Reactant: Nc1ccc(-c2c(F)cccc2C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1ccc(-c2c(F)cccc2C(F)(F)F)cc1N
Temperature: 80 °C
Reaction time: 14 h
Yield: 98 %

Procedure:
2′-Fluoro-3-nitro-6′-trifluoromethyl-biphenyl-4-ylamine (754 mg, 2.51 mmol, as prepared in the previous step) was placed in a 40 mL vial equipped with a magnetic stir bar, then EtOH (20 mL) and water (5 mL) were added. Ammonium chloride (10 eq., 1.34 g, 25.1 mmol) was added as a solid, and then iron powder (5 eq., 701 mg, 12.6 mmol) was added. The vial was tightly capped and placed in a heating block where the reaction was stirred at 80° C. for 14 h. The reaction was cooled to rt, poured into water, and extracted three times with EtOAc (40 mL). The combined organic extracts were dried over anhydrous MgSO4, filtered, and the solvent was removed under reduced pressure to give 662 mg (98%) of the title compound. 1H-NMR (400 MHz, CDCl3) δ: 7.52 (d, J=7.8 Hz, 1H), 7.39 (td, J=7.9, 5.7 Hz, 1H), 7.25-7.32 (m, 1H), 6.71-6.77 (m, 1H), 6.60-6.67 (m, 2H), 3.45 (br. s., 4H).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]3[N:18]=[C:19]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:20][C:21]=3[C:22]([F:25])([F:24])[F:23])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.Cl[C:33]([O:35][C:36]1[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=1)=[O:34].N1C=CC=CC=1>C(Cl)Cl>[N+:42]([C:39]1[CH:38]=[CH:37][C:36]([O:35][C:33]([N:2]2[CH2:7][CH2:6][CH:5]([C:8]3[CH:9]=[CH:10][C:11]([NH:14][C:15]([C:17]4[N:18]=[C:19]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[O:20][C:21]=4[C:22]([F:23])([F:24])[F:25])=[O:16])=[CH:12][CH:13]=3)[CH2:4][CH2:3]2)=[O:34])=[CH:41][CH:40]=1)([O-:44])=[O:43]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: O=C(Nc1ccc(C2CCNCC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ccc(C2CCN(C(=O)Oc3ccc([N+](=O)[O-])cc3)CC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.1 %

Procedure:
To a mixture of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-piperidin-4-yl-phenyl)-amide hydrochloride salt (2.0 g, 4.43 mmol) in methylene chloride (20 mL) at room temperature was added p-nitrophenyl chloroformate (1.11 g, 5.52 mmol) followed by pyridine (1.1 mL, 13.6 mmol). The mixture was stirred at room temperature overnight. The slurry was filtered and the filtrate was evaporated to give a crude material (2.4 g). The crude was triturated with methanol and filtration gave 4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperidine-1-carboxylic acid 4-nitro-phenyl ester (850 mg, crude) as a white solid, which was directly used in the next step without further purification. LCMS calcd for C29H23F3N4O6 (m/e) 580, obsd 581 (M+H). The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:12]([OH:14])=[O:13])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[N:15]([O-])=O.[Na+].Cl[Sn]Cl.O>Cl.O>[NH:1]([C:2]1[C:3]([C:12]([OH:14])=[O:13])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)[NH2:15]
Reactant: Nc1cc2ccccc2cc1C(=O)O
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: NNc1cc2ccccc2cc1C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 3-amino-2-naphthoic acid (15 g, 66.8 mmol) in conc. HCl (100 ml) and water (100 ml) at 0° C. was added NaNO2 (9.22 g, 69 mmol) in 1 g portions while maintaing the reaction temperature below 0° C. After 30 min below 0° C., SnCl2·H2O (75 g) was added in portions over 20 min. The ice bath was removed and stirred at ambient temperature for 1 h. Reaction was filtered and the filter cake washed with water and air dried. The crude material containing tin (II) salts was used as is and gave a mp>300° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=O.[CH:12]1([CH2:15][CH:16]([C:19]2[CH:20]=[CH:21][C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][CH:24]=2)[CH2:17][NH2:18])[CH2:14][CH2:13]1>>[Cl:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:2]([Cl:1])[C:3]=1[C:4]([NH:18][CH2:17][CH:16]([C:19]1[CH:20]=[CH:21][C:22]([C:25]([F:28])([F:26])[F:27])=[N:23][CH:24]=1)[CH2:15][CH:12]1[CH2:13][CH2:14]1)=[O:6]
Reactant: NCC(CC1CC1)c1ccc(C(F)(F)F)nc1
Reactant: O=C(O)c1c(Cl)cccc1Cl
Product: O=C(NCC(CC1CC1)c1ccc(C(F)(F)F)nc1)c1c(Cl)cccc1Cl

Procedure:
The racemic mixture which was prepared in a similar manner to example 3a from 2,6-dichlorobenzoic acid and 3-cyclopropyl-2-(2-(trifluoromethyl)pyridin-5-yl)propan-1-amine was separated into the two enantiomers by preparative SFC to yield the title compound LCMS (MH+): m/z=417.1, tR (minutes, Method G)=2.50. [α]D20=+20.64 (c=4.7 mg/mL,CHCl3)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH3:15])([CH3:14])[CH2:10][NH:11][CH2:12][CH:13]=2)=[CH:4][CH:3]=1.C(O)(=O)C>CO.[OH-].[OH-].[Pd+2]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][C:9]2([CH3:15])[CH3:14])=[CH:4][CH:3]=1
Reactant: CC1(C)CNCC=C1c1ccc(F)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: CC1(C)CNCCC1c1ccc(F)cc1
Reaction time: 48 h
Yield: 97.3 %

Procedure:
A mixture of 4-(4-fluorophenyl)-3,3-dimethyl-1,2,3,6-tetrahydropyridine (450 mg, 2.192 mmol), palladium hydroxide on carbon (308 mg, 2.192 mmol), and acetic acid (1.5 mL, 26.2 mmol) in methanol (10 mL) was degassed under nitrogen/vacuum, then hydrogenated at 50 psi for two days. The catalyst was removed by filtration and rinsed with methanol, and the filtrate was concentrated in vacuo to yield the title compound (442 mg, 2.132 mmol, 97% yield) as a pale yellow oil. MS (ESI+)=208.29, (M+H)+.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[C:8]2[N:9]=[C:10]([NH2:12])[S:11][C:7]=2[C:6]2[CH:13]=[N:14][NH:15][C:5]=2[CH:4]=1.[Cl:18][CH2:19][C:20](Cl)=[O:21]>O1CCOCC1>[Cl:18][CH2:19][C:20]([NH:12][C:10]1[S:11][C:7]2[C:6]3[CH:13]=[N:14][N:15]([C:20](=[O:21])[CH2:19][Cl:18])[C:5]=3[CH:4]=[C:3]([C:2]([F:1])([F:16])[F:17])[C:8]=2[N:9]=1)=[O:21]
Reactant: Nc1nc2c(C(F)(F)F)cc3[nH]ncc3c2s1
Reactant: O=C(Cl)CCl
Solvent: C1COCCO1
Product: O=C(CCl)Nc1nc2c(C(F)(F)F)cc3c(cnn3C(=O)CCl)c2s1
Temperature: 25 °C
Yield: 82.7 %

Procedure:
A mixture of 0.26 g (1.00 mmol) of 4-trifluoromethyl-6H-pyrazolo[4′,3′:3,4]benzo[1,2-d]thiazol-2-ylamine, 1.0 ml (12.6 mmol) of chloroacetyl chloride and 4 ml of 1,4-dioxane was heated under reflux for 3 hours. After the completion of the reaction was confirmed by HPLC, the reaction mixture was cooled to room temperature and poured into ice-water. The precipitated solid was collected by filtration and was washed with water to give 0.34 g (yield: 77%) of 2-chloro-N-[6-(2-chloro-acetyl)-4-trifluoromethyl-6H-pyrazolo[4′,3′:3,4]benzo[1,2-d]thiazol-2-yl]-acetamide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([N:12]1[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=3)[CH2:14][CH2:13]1)[N:8]([C:26]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:27]=1[O:36][CH3:37])[CH:7]2[CH2:38][C:39]([OH:41])=[O:40].S(=O)(=O)(O)O.[CH3:47]O>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([N:12]1[CH2:13][CH2:14][N:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=3)[CH2:16][CH2:17]1)[N:8]([C:26]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:27]=1[O:36][CH3:37])[CH:7]2[CH2:38][C:39]([O:41][CH3:47])=[O:40]
Reactant: CO
Reactant: COc1cccc(N2CCN(C3=Nc4c(F)cccc4C(CC(=O)O)N3c3cc(C(F)(F)F)ccc3OC)CC2)c1
Agent: O=S(=O)(O)O
Solvent: CCO
Product: COC(=O)CC1c2cccc(F)c2N=C(N2CCN(c3cccc(OC)c3)CC2)N1c1cc(C(F)(F)F)ccc1OC
Yield: 81.8 %

Procedure:
(±)-{8-Fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-(2-methoxy-5-trifluoromethylphenyl)-3,4-dihydroquinazolin-4-yl}acetic acid (148 g) is dissolved in methanol (1480 g), then concentrated sulphuric acid (21.5 ml) is added. The mixture is stirred under reflux for 6 h, then cooled and concentrated to ca. one third of the original volume in vacuo. Water (400 ml) and dichloromethane (400 ml) are added, then the phases are separated. The organic phase is extracted with saturated sodium hydrogencarbonate solution (two times 375 ml, diluted with 300 ml of water), dried over sodium sulphate and concentrated to give a foamy residue. This is dissolved twice in succession in ethanol (400 ml each) and concentrated, and subsequently dried in vacuo for 18 h using entraining nitrogen. A total of 124 g of methyl {8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}acetate are thus obtained as an amorphous solid, corresponding to 81.9% of theory.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[N:5]=[CH:4][C:3]=1[C:16]([N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:20][CH2:19]1)=[O:17].[NH2:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[NH:36][CH:35]=[CH:34]2>>[CH2:14]([O:13][C:11]([C:10]1[CH:9]=[N:8][N:7]2[C:2]([NH:30][C:31]3[CH:32]=[C:33]4[C:37](=[CH:38][CH:39]=3)[NH:36][CH:35]=[CH:34]4)=[C:3]([C:16]([N:18]3[CH2:23][CH2:22][CH:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:20][CH2:19]3)=[O:17])[CH:4]=[N:5][C:6]=12)=[O:12])[CH3:15]
Reactant: CCOC(=O)c1cnn2c(Cl)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Reactant: Nc1ccc2[nH]ccc2c1
Product: CCOC(=O)c1cnn2c(Nc3ccc4[nH]ccc4c3)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Yield: 100.5 %

Procedure:
In the same manner as in Example 19, step 5 and using 7-chloro-3-ethoxycarbonyl-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine (0.15 g, 0.36 mmol) obtained in Example 19, step 4 and 5-aminoindole (0.072 g, 0.54 mmol), the title compound (0.184 g, 99%) was obtained.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=3)=[CH:13][C:12]2=[O:26])=[CH:5][CH:4]=1.[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>CN(C=O)C>[CH3:25][C:24]1[C:19]([CH2:18][O:17][C:14]2[CH:15]=[CH:16][N:11]([CH2:10][CH2:9][C:6]3[CH:7]=[CH:8][C:3]([CH2:2][N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)=[CH:4][CH:5]=3)[C:12](=[O:26])[CH:13]=2)=[N:20][CH:21]=[CH:22][CH:23]=1
Reactant: C1CCNC1
Reactant: Cc1cccnc1COc1ccn(CCc2ccc(CBr)cc2)c(=O)c1
Solvent: CN(C)C=O
Product: Cc1cccnc1COc1ccn(CCc2ccc(CN3CCCC3)cc2)c(=O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 100 mg (0.24 mmol) 1-[2-(4-bromomethyl-phenyl)-ethyl]-4-(3-methyl-pyridin-2-ylmethoxy)-1H-pyridin-2-one (example 14.1b) in 1.5 mL DMF is added 79 μL (0.97 mmol) pyrrolidine at RT. The reaction mixture is stirred for 2 h at RT and is directly transferred to a reverse HPLC for purification (Zorbax stable bond, C18; water (0.15% formic acid)/acetonitrile 95:5 to 10:90).
Reaction SMILES: Cl[C:2]1([CH2:7][C:8]([Cl:11])([Cl:10])Cl)[O:5][C:4](=[O:6])[CH2:3]1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C([O-])(O)=O.[Na+]>C(Cl)Cl.CC(OC)(C)C>[Cl:11][C:8]([Cl:10])=[CH:7][C:2](=[O:5])[CH2:3][C:4]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=[O:6]
Reactant: C1COCCN1
Reactant: O=C1CC(Cl)(CC(Cl)(Cl)Cl)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: COC(C)(C)C
Product: O=C(C=C(Cl)Cl)CC(=O)N1CCOCC1
Temperature: 15 °C
Yield: 72927.5 %

Procedure:
Two separate solutions of 1 (62.5 g, 0.26 mmol) and morpholine (24.0 g, 0.28 mol) in DCM (120 ml) were added simultaneously to a mixture of NaHCO3 (44.0 g, 0.52 mol) in dry DCM (300 ml). The reaction was maintained at 15° C. over 140 minutes with stirring. The reaction was filtered, washed with DCM (3×100 ml) and the combined organic layers were concentrated in vacuo to a slurry which was then passed through a short silica pad, and further washed with DCM (4×100 ml). The combined organic layers were concentrated in vacuo, suspended in hexane (400 ml) and stirred for 1 hour, filtered and dried to give a cream solid. The solid was suspended in TBME (100 ml), stirred for 15 minutes, filtered, washed with TBME and dried to give 2 as a white powder (47.8 g, 72%). m/z (LC-MS, ESP): 252 (M++1).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[N:9]([C@@H:10]2[CH2:19][C:18]3[C:13](=[C:14]([F:21])[CH:15]=[C:16]([F:20])[CH:17]=3)[O:12][CH2:11]2)[C:8](=[S:22])[NH:7][CH:6]=1.[CH3:23][CH:24](O)[CH3:25]>O1CCCC1>[CH2:23]([NH:2][CH2:3][CH2:4][C:5]1[N:9]([C@@H:10]2[CH2:19][C:18]3[C:13](=[C:14]([F:21])[CH:15]=[C:16]([F:20])[CH:17]=3)[O:12][CH2:11]2)[C:8](=[S:22])[NH:7][CH:6]=1)[C:24]1[CH:25]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)O
Reactant: NCCc1c[nH]c(=S)n1[C@H]1COc2c(F)cc(F)cc2C1
Agent: Cl
Solvent: C1CCOC1
Product: Fc1cc(F)c2c(c1)C[C@@H](n1c(CCNCc3ccccc3)c[nH]c1=S)CO2
Temperature: 22.5 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
(R)-5-(2-(benzylamino)ethyl)-1-(6,8-difluorochroman-3-yl)-1H-imidazole-2(3H)-thione (12 g, 29.9 mmol) was dissolved with heating to reflux in Tetrahydrofuran (300 ml), the solution was cooled to 5-10° C., Water (510 ml) was added slowly (approx 10 min) with stirring. The mixture was stirred for 1 h, solid was collected, washed with water, dried to give 11.73 g of product, by HPLC 1% of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride and 1% of less polar impurity. The product was dissolved in Tetrahydrofuran (300 ml) with heating to reflux, 2-Propanol (150 ml) was added, the solution was concentrated to approx 100 ml (crystallisation occurred), stirred in ice for 1.5 h. Solid was collected, washed with 2-propanol, dried to give 11.2 g of product, by HPLC 0.8% of (R)-5-(2-aminoethyl)-1-(6,8-difluorochroman-3-yl)-1H-imidazole-2(3H)-thione hydrochloride and 0.5% of less polar impurity. The product was dissolved in Tetrahydrofuran (300 ml) with heating to reflux, 2-Propanol (150 ml) was added, the solution was concentrated to approx 100 ml (crystallisation occurred), stirred at 20-25° C. for 1 h. Solid was collected, washed with 2-propanol, dried to give (R)-5-(2-(benzylamino)ethyl)-1-(6,8-difluorochroman-3-yl)-1H-imidazole-2(3H)-thione (10.22 g, 25.5 mmol, 85% yield).,
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=O)[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[NH2:14][C@H:15]([C:24]([OH:26])=[O:25])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1.[BH4-].[Na+].Cl>CO>[CH:2]([O:25][C:24](=[O:26])[CH:15]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([OH:23])=[CH:21][CH:22]=1)[NH:14][CH:9]([CH2:8][C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=1)[C:10]([O:12][CH:5]([CH3:6])[CH3:4])=[O:11])([CH3:7])[CH3:3]
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Reactant: O=C(O)C(=O)Cc1ccc(O)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)OC(=O)C(Cc1ccc(O)cc1)NC(Cc1ccc(O)cc1)C(=O)OC(C)C
Temperature: 60 °C
Reaction time: 6 h

Procedure:
9.01 g (50.0 mmol) of 4-hydroxyphenylpyruvic acid and 9.06 g (50.0 mmol) of tyrosine are dissolved in 60 ml of methanol and stirred for six hours at 60° C. Then, it is allowed to cool to room temperature and 0.76 g (20 mmol) of sodium borohydride is added. It is allowed to stir overnight and then the reaction mixture is mixed carefully with diluted hydrochloric acid until no more gas generation can be observed. The reaction mixture is concentrated by evaporation and dried in an oil pump vacuum for several hours at 100° C. The residue is taken up in isopropanol. Hydrogen chloride gas is introduced until saturation is achieved, stirred for two hours at room temperature and then for eight hours at 85° C. Then, it is concentrated by evaporation, the residue is dispersed between ethyl acetate and sodium bicarbonate solution, the organic phase is dried on sodium sulfate, filtered and concentrated by evaporation. The residue is chromatographed on silica gel with use of hexane/ethyl acetate as mobile solvent. The fractions that contain the pure product are combined and concentrated by evaporation.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C(OC(=O)[NH:14][CH2:15][CH2:16][N:17]1[CH:21]=[CH:20][NH:19][C:18]1=[O:22])(C)(C)C>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:14][CH2:15][CH2:16][N:17]1[CH:21]=[CH:20][NH:19][C:18]1=[O:22]
Reactant: CC(C)(C)OC(=O)NCCn1cc[nH]c1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCn1cc[nH]c1=O
Reaction time: 3 h

Procedure:
Add trifluoro-acetic acid (10 mL) to a solution of [2-(2-oxo-2,3-dihydro-imidazol-1-yl)-ethyl]-carbamic acid tert-butyl ester (2.5 g, 11 mmol) in dichloromethane (10 mL). Stir the mixture for 3 hours. Remove most of the solvent and trifluoro-acetic acid on a rotovap and dry the yellowish thick oil under vacuum to get the product. GCMS (EI) m/z 127 M+.
Reaction SMILES: [OH:1][CH:2](CO)[CH2:3][C@H:4]([NH:15][C:16]([C:18]1[C:19]2[CH:26]=[N:25][N:24]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[C:20]=2[CH:21]=[N:22][CH:23]=1)=[O:17])[C:5]1[CH:10]=[CH:9][N:8]=[C:7]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:6]=1>CC(C)=O.O>[CH3:14][S:11]([C:7]1[CH:6]=[C:5]([C@@H:4]([NH:15][C:16]([C:18]2[C:19]3[CH:26]=[N:25][N:24]([C:27]4[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=4)[C:20]=3[CH:21]=[N:22][CH:23]=2)=[O:17])[CH2:3][CH:2]=[O:1])[CH:10]=[CH:9][N:8]=1)(=[O:13])=[O:12]
Reactant: CS(=O)(=O)c1cc([C@H](CC(O)CO)NC(=O)c2cncc3c2cnn3-c2ccc(F)cc2)ccn1
Solvent: O
Solvent: CC(C)=O
Product: CS(=O)(=O)c1cc([C@H](CC=O)NC(=O)c2cncc3c2cnn3-c2ccc(F)cc2)ccn1
Reaction time: 18 h

Procedure:
To a room temperature solution of 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid [(S)-3,4-dihydroxy-1-(2-methanesulfonyl-pyridin-4-yl)-butyl]-amide (0.710 g, 1.42 mmol) in acetone (18 mL) and water (9 mL) was added NaIO4 (608 mg, 2.84 mmol). After 18 hours, the mixture was filtered through diatomaceous earth washing with acetone (3×20 mL). The acetone was removed in vacuo and the aqueous layer was diluted with brine (50 mL) and extracted with EtOAc (3×50 mL). The combined organics layers were dried over magnesium sulfate, filtered, and evaporated to afford 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid [(S)-1-(2-methanesulfonyl-pyridin-4-yl)-3-oxo-propyl]-amide as white solid which was used without purification.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][N:7]([C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[CH:13]=2)[C:8]=1[C:9]([NH2:11])=[O:10])([OH:3])=[O:2].[CH3:20]O>>[CH3:20][O:2][C:1]([C:4]1[CH:5]=[N:6][N:7]([C:12]2[CH:13]=[C:14]([CH3:19])[CH:15]=[C:16]([CH3:18])[CH:17]=2)[C:8]=1[C:9]([NH2:11])=[O:10])=[O:3]
Reactant: CO
Reactant: Cc1cc(C)cc(-n2ncc(C(=O)O)c2C(N)=O)c1
Product: COC(=O)c1cnn(-c2cc(C)cc(C)c2)c1C(N)=O

Procedure:
A 1.1 g portion of the compound of Example 1 was suspended in 20 ml of methanol and hydrogen chloride gas was bubbled through the mixture for 1 minute. The mixture was then heated under reflux for 2 hours, and was poured into 50 ml of ice-water. The aqueous mixture was made basic with sodium hydroxide and was filtered, and the solids were dried under vacuum and recrystallized from toluene to obtain 0.14 g of the desired product, m.p. 179°-180°.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.C[O-].[Na+].[F:14][C:15]([F:22])([F:21])[C:16](OCC)=[O:17]>CO>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH2:9][C:16](=[O:17])[C:15]([F:22])([F:21])[F:14])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(F)(F)F
Reactant: CC(=O)c1ccc(C)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(C(=O)CC(=O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 93.9 %

Procedure:
4′-Methylacetophenone (5.26 g, 39.2 mmol) was dissolved in 25 mL of methanol under argon and 12 mL (52.5 mmol) sodium methoxide in methanol (25%) was added. The mixture was stirred for 5 minutes and 5.5 mL (46.2 mmol) ethyl trifluoroacetate was added. After refluxing for 24 hours, the mixture was cooled to room temperature and concentrated. 100 mL 10% HCl was added and the mixture extracted with 4×75 mL ethyl acetate. The extracts were dried over MgSO4, filtered and concentrated to afford 8.47 g (94%) of a brown oil which was carried on without further purification.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[C:7](Cl)[N:6]=[C:5]([Cl:10])[N:4]=1.[F-:11].[K+]>S1(CCCC1)(=O)=O>[Cl:10][C:5]1[N:4]=[C:3]([CH2:2][Cl:1])[CH:8]=[C:7]([F:11])[N:6]=1
Reactant: ClCc1cc(Cl)nc(Cl)n1
Reactant: [F-]
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Product: Fc1cc(CCl)nc(Cl)n1
Temperature: 0 °C

Procedure:
5 g (0.027 mol) of 4-chloromethyl-2,6-dichloro-pyrimidine (see Examples 73 and 92) and 3.3 g (0.056 mol) of anhydrous potassium fluoride in 8 ml of sulpholane are heated at 140° C. for 24 hours. The mixture is then cooled to 0° C. and filtered over silica gel using diethyl ether/n-hexane (1:4). After removing the solvent by evaporation there is obtained 2-chloro-4-chloromethyl-6-fluoro-pyrimidine in the form of a yellow oil, 1H-NMR (CDCl3): 4.70 (s, CH2Cl), 7.30 (d, JFH =2 Hz, H).