Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[CH:4][C:3]=1[N+:14]([O-])=O.[Cl-].[NH4+]>C(O)C.O.[Fe]>[CH3:1][C:2]1[C:3]([NH2:14])=[CH:4][CH:5]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:7]=1
Reactant: Cc1nc(N2CCOCC2)ccc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Cc1nc(N2CCOCC2)ccc1N
Yield: 39.5 %

Procedure:
A suspension of 4-(6-methyl-5-nitro-2-pyridinyl)morpholine (500 mg, 2.240 mmol), iron powder (375 mg, 6.72 mmol) and ammonium chloride (60 mg, 1.120 mmol) in ethanol (15 mL) and water (5 mL) was heated at reflux for 2 hours. The reaction mixture was filtered through a pad of celite and the pad washed with further ethyl acetate. The combined filtrate and washings were separated between ethyl acetate and saturated sodium bicarbonate and the organic phase was washed with water then brine. The organics were then separated, dried over magnesium sulphate and evaporated in vacuo to give the title compound (171 mg) as a pale brown solid. LCMS (2 min, formic) Rt 0.30 min, m/z (ES+) 194 (M+H).
Reaction SMILES: [Br:1]Br.[O:3]=[C:4]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:6][CH2:5]1>C(Cl)(Cl)Cl>[Br:1][CH:10]1[C:4](=[O:3])[CH2:5][CH2:6][N:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:8][CH2:9]1
Reactant: CCOC(=O)N1CCCC(=O)CC1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1CCC(=O)C(Br)CC1
Reaction time: 8 h

Procedure:
79.9 g (500 mmol) bromine are added to a solution of 92.7 g (500 mmol) ethyl 4-oxo-azepan-1-carboxylate in 350 mL chloroform and the reaction is stirred overnight. The reaction solution is washed three times with saturated NaHCO3 solution, the organic phase is dried over Na2SO4 and the solvent is eliminated i.vac. The product is further reacted without purification.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[N:20][C:6]1=2)=[O:4].[N:21]1([CH2:26][C@@H:27]2[CH2:31][CH2:30][CH2:29][NH:28]2)[CH2:25][CH2:24][CH2:23][CH2:22]1.C(OCC)(=O)C>C(O)C>[N:21]1([CH2:26][C@@H:27]2[CH2:31][CH2:30][CH2:29][N:28]2[CH2:2][C:3]([N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:9](=[O:16])[NH:8][C:7]3[CH:17]=[CH:18][CH:19]=[N:20][C:6]2=3)=[O:4])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=C1Nc2cccnc2N(C(=O)CCl)c2ccccc21
Reactant: C1CN[C@H](CN2CCCC2)C1
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C1Nc2cccnc2N(C(=O)CN2CCC[C@H]2CN2CCCC2)c2ccccc21

Procedure:
The title compound is prepared analogously to Example 31 from 11-(chloroacetyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and (S)-(+)-2-[(1-pyrrolidinyl)methyl]pyrrolidine to give colorless crystals, mp. 192°-193° C. (ethyl acetate). [α]D20 =-18.1° (ethanol).
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:18]3[CH2:19][N:20]([C:23](=[O:25])[CH3:24])[CH2:21][CH2:22][C:17]=3[NH:16][N:15]=2)=[CH:10][CH:9]=1.Br[CH2:27][CH2:28][CH2:29][Cl:30].O>CN(C=O)C>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[C:18]3[CH2:19][N:20]([C:23](=[O:25])[CH3:24])[CH2:21][CH2:22][C:17]=3[N:16]([CH2:27][CH2:28][CH2:29][Cl:30])[N:15]=2)=[CH:12][CH:13]=1
Reactant: CC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2C1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)N1CCc2c(c(-c3ccc(Cl)cc3)nn2CCCCl)C1
Reaction time: 0.25 h
Yield: 55.7 %

Procedure:
Cs2CO3 (2.66 g, 8.2 mmol) was added to a solution of 1-[3-(4-chloro-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone (1.0 g, 5.4 mmol) in DMF (10 mL) and stirred for 15 min. 1-Bromo-3-chloropropane (1.28 g, 8.2 mmol) was added and stirred under N2 at room temperature for 36 h. Water (50 mL) was added to the reaction and stirred for 5 min. The product precipitated out. The aqueous portion was decanted and water was added to the residue and decanted again. The semisolid was taken up in CH2Cl2 and passed through a short plug of SiO2 (5% MeOH/EtOAc) to obtain 1.06 g (83%) of a pale yellow semisolid. MS (electrospray): exact mass calculated for C17H19Cl2N3O, 351.09; m/z found, 352.0 [M+H]+. 1H NMR (500 MHz, CDCl3, a mixture of 1:1 rotamers): 7.60 (d, J=8.3 Hz, 1H), 7.53 (d, J=8.3 Hz, 1H), 7.40 (d, J=8.3 Hz, 1H), 7.36 (d, J=8.3 Hz, 1H), 4.77 (s, 1H), 4.61 (s, 1H), 4.20 (t, J=6.2 Hz, 2H), 3.94 (t, J=5.8 Hz, 1H), 3.76 (t, J=5.8 Hz, 1H), 3.52 (q, J=6.1 Hz, 2H), 2.84 (t, J=5.5 Hz, 1H), 2.77 (t, J=5.6 Hz, 1H), 2.37 (sextet, J=6.1 Hz, 2 H), 2.21 (s, 1.5 H), 2.16 (s, 1.5 H).
Reaction SMILES: [NH:1]1[C:9]2[CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5][C:4]=2[CH:3]=[C:2]1[C:17]([O:19][CH2:20][CH3:21])=[O:18].[H-].[Na+].[CH3:24]I>C1COCC1>[CH3:24][N:1]1[C:9]2[CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5][C:4]=2[CH:3]=[C:2]1[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)c1cc2c([nH]1)CCN(C(=O)OC(C)(C)C)C2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2c(n1C)CCN(C(=O)OC(C)(C)C)C2
Temperature: 25 °C

Procedure:
To a solution of 5-tert-butyl 2-ethyl 1,4,6,7-tetrahydro-5H-pyrrolo[3,2-c]pyridine-2,5-dicarboxylate (1.0 eq) in THF at 0° C. was added NaH (1.2 eq) and stirred for half an hour at room temperature. Methyl iodide (1.3 eq) was added and resulting reaction mixture was stirred for 3 hrs. Reaction mixture was then quenched with water and extracted with ethyl acetate, dried over sodium sulphate and concentrated to dryness. Crude mass was then purified by silica gel column chromatography to afford 5-tert-butyl 2-ethyl 1-methyl-1,4,6,7-tetrahydro-5H-pyrrolo[3,2-c]pyridine-2,5-dicarboxylate.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[N:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.[CH2:17]([NH2:21])[CH2:18][CH2:19][CH3:20]>C(O)(C)(C)C>[CH2:17]([NH:21][C:3]([NH:2][CH3:1])=[N:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)[CH2:18][CH2:19][CH3:20]
Reactant: CCCCN
Reactant: CN=C=Nc1ccccc1N1CCOCC1
Solvent: CC(C)(C)O
Product: CCCCNC(=Nc1ccccc1N1CCOCC1)NC

Procedure:
A mixture of N-methyl-N'-(2-morpholinophenyl)carbodiimide (1 g), n-butylamine (0.5 g) and t-butanol (5 ml) was heated at 90°-95° C. for four hours. The solvent was removed by evaporation and the residue dissolved in dichloromethane (100 ml) and the resulting solution was washed with water, dried and filtered. Removal of the solvent gave 1-(n-butyl)-2-(2-morpholinophenyl)-3-methylguanidine which was converted into its monofumarate salt (m.p. 178°-179° C.).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1.[OH:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].CCOCC>CC(C)=O>[N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:12]=[CH:13][C:4]=1[CH2:3][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: ClCc1ccc2ccccc2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC(C)=O
Product: O=Cc1ccc(OCc2ccc3ccccc3n2)cc1
Temperature: 25 °C

Procedure:
A mixture containing 2-(chloromethyl)quinoline hydrochloride (15 g), 4-hydroxybenzaldehyde (8.56 g) and anhydrous potassium carbonate (29 g) was heated under reflux in acetone (300 mL) for 86 h. After cooling to room temperature, ether (400 mL) was added and the mixture was filtered on celite. The filtrate was evaporated to dryness under reduced pressure and purified by flash chromatography using 15% ethyl acetate/hexane. The title compound was obtained after recrystallization from ethyl acetate/hexane m.p. 89°-90°.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.[CH3:13][C:14]([CH3:21])([CH3:20])[C:15](=O)[CH2:16][C:17]#[N:18]>>[C:14]([C:15]1[CH:16]=[C:17]([NH2:18])[N:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:11])([F:12])[F:1])=[CH:8][CH:7]=2)[N:10]=1)([CH3:21])([CH3:20])[CH3:13]
Reactant: CC(C)(C)C(=O)CC#N
Reactant: NNc1ccc(C(F)(F)F)cc1
Product: CC(C)(C)c1cc(N)n(-c2ccc(C(F)(F)F)cc2)n1
Yield: 60.1 %

Procedure:
The title compound was prepared from 4-(trifluoromethyl)-phenylhydrazine (1.41 g, 8.0 mmol) and 4,4-dimethyl-3-oxopentanenitrile (1.0 g, 8.0 mmol) using the procedure in Example 161A Step 3 to give to give 3-tert-butyl-1-(4-(trifluoromethyl)phenyl)-1H-pyrazol-5-amine (1.36 g, 4.81 mmol, 60%). 1H NMR (300 MHz, DMSO-d6) δ 7.81 (d, 2H), 7.80 (d, 2H), 5.44 (s, 3H), 1.22 (s, 9H); LC-MS (ESI) m/z 284 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[CH:10][C:11]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[S:12])=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:34][O:35][C:36]1[CH:37]=[C:38]([CH:42]=[C:43]([O:47][CH3:48])[C:44]=1[O:45][CH3:46])[C:39](Cl)=[O:40].O>C(Cl)Cl>[CH3:26][O:25][C:22]1[CH:21]=[CH:20][C:19]([C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[CH:10][C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:39](=[O:40])[C:38]3[CH:37]=[C:36]([O:35][CH3:34])[C:44]([O:45][CH3:46])=[C:43]([O:47][CH3:48])[CH:42]=3)[CH2:15][CH2:14]2)=[S:12])=[CH:24][CH:23]=1
Reactant: COc1ccc(C(=CC(=S)N2CCNCC2)c2ccc(OC)cc2)cc1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COc1ccc(C(=CC(=S)N2CCN(C(=O)c3cc(OC)c(OC)c(OC)c3)CC2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 357.2 %

Procedure:
1.049 g of 1-[3,3-bis(4-methoxyphenyl)thioacryloyl]piperazine [prepared as described in step (b) above] and 0.29 ml of triethylamine were dissolved in 30 ml of methylene chloride, and 0.157 g of 3,4,5-trimethoxybenzoyl chloride were added, whilst ice-cooling, to the resulting solution. The reaction mixture was then stirred for 1 hour at room temperature, after which it was poured into water and extracted twice with methylene chloride. The combined extracts were washed with 10% w/v aqueous hydrochloric acid, with a saturated aqueous solution of sodium bicarbonate and with water, in that order, after which they were dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography through 40 g of silica gel and by medium pressure liquid chromatography using a Lobar B column using mixtures of methylene chloride and ethyl acetate ranging from 9:1 to 4:1 by volume as eluent, to give 1.368 g of the title compound as a yellow powder.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]2[CH2:13][C@@H:12]([C:14](=[O:21])[CH2:15][C:16](OCC)=[O:17])[CH2:11][CH2:10][N:9]2[C:22]([O:24][CH3:25])=[O:23])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl.[NH2:29]O.Cl>CO.CO.O>[CH:1]1([CH2:7][C@H:8]2[CH2:13][C@@H:12]([C:14]3[O:21][NH:29][C:16](=[O:17])[CH:15]=3)[CH2:11][CH2:10][N:9]2[C:22]([O:24][CH3:25])=[O:23])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](CC2CCCCC2)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1CC1CCCCC1
Reaction time: 0.5 h
Yield: 53.1 %

Procedure:
A solution of cis-methyl 2-(cyclohexylmethyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate, from a preparation of Example 20, Step 1 (1.28 g, 3.62 mmol) in MeOH (3 mL) was added dropwise to a solution of NaOH (0.159 g) in MeOH/H2O (3 mL/0.2 mL) at −30° C. After stirring for 10 minutes a solution of hydroxylamine hydrochloride (0.50 g, 7.24 mmol) and NaOH (0.29 g, 7.24 mmol) in methanol/water (5 mL/5 mL) was added at −30° C. Stirring was continued for 30 minutes at −30° C. The solution was added dropwise to HCl (6M) at 80° C. Stirred 30 minutes at 80° C. The reaction mixture was partitioned between water and ethyl acetate. The organic phase was isolated, dried with Na2SO4, filtered through Celite® and the solvent was evaporated. Acidic reversed phase chromatography, gradient 35% to 75% acetonitrile gave cis-methyl 2-(cyclohexylmethyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (0.62 g, 53.1%). Chiral separation using Chiralpac IC, mobile phase heptane/isopropyl alcohol 80/20 at the temperature 40° C. gave (2R,4R)-methyl 2-(cyclohexylmethyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (0.28 g), e.e. 98.5% and (2S,4S)-methyl 2-(cyclohexylmethyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (0.27 g), e.e 98.5%. 1H NMR (600 MHz, cdcl3, RR) δ 0.67-0.88 (m, 2H), 0.98-1.20 (m, 5H), 1.28 (dd, 1H), 1.56 (dd, 5H), 1.75-1.86 (m, 2H), 1.92-2.06 (m, 2H), 2.87-2.99 (m, 1H), 3.02-3.15 (m, 1H), 3.65 (s, 3H), 3.88 (dd, 1H), 4.15 (p, 1H), 5.65 (d, 1H). [α]20D −30.7 (MeCN, c=1); 1H NMR (600 MHz, cdcl3, SS) δ 0.70-0.87 (m, 2H), 0.97-1.20 (m, 5H), 1.28 (dd, 1H), 1.51-1.65 (m, 5H), 1.77-1.85 (m, 2H), 1.96-2.05 (m, 2H), 2.87-2.96 (m, 1H), 3.03-3.14 (m, 1H), 3.65 (s, 3H), 3.88 (dd, 1H), 4.15 (p, 1H), 5.65 (d, 1H) [α]20D +29.9 (MeCN, c=1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:4][CH:3]=1.[C:19]1(=[O:29])[NH:23][C:22](=[O:24])[C:21]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:23]2[C:19](=[O:29])[C:20]3[C:21](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:22]2=[O:24])[CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:4][CH:3]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)NCC(O)c1ccc(Cl)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC(c1ccc(Cl)cc1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
At RT, 2.61 g of rac-tert-butyl [2-(4-chlorophenyl)-2-hydroxyethyl]carbamate (Example 45A, 9.62 mmol), 1.42 g of phthalimide (9.62 mmol) and 3.78 g of triphenylphosphine (14.43 mmol) were initially charged in abs. THF. 4.03 g (14.43 mmol) of diisopropyl azodicarboxylate were then added dropwise, and the mixture was stirred at RT for 30 min. The reaction mixture was concentrated and purified by silica gel chromatography (mobile phase: cyclohexane:ethyl acetate 10:1). This gave 2.92 g of the title compound (55% of theory, purity about 73%).
Reaction SMILES: O=[C:2]1CN[C:5](=[O:8])[CH2:4][NH:3]1.C=[O:10].[OH:11][PH:12]([OH:14])=[O:13].P(Cl)(Cl)Cl>C(O)(=O)C>[P:12]([CH2:2][NH:3][CH2:4][C:5]([OH:8])=[O:10])([OH:14])([OH:11])=[O:13]
Reactant: O=[PH](O)O
Reactant: C=O
Reactant: O=C1CNC(=O)CN1
Solvent: CC(=O)O
Solvent: ClP(Cl)Cl
Product: O=C(O)CNCP(=O)(O)O

Procedure:
The sequence of reactions in Reaction Scheme 9a is comparable to those set forth in Reaction Scheme 9 except that N-acetylglycine XVIII is deacylated to form 2,5-diketopiperazine XXX. 2,5-diketopiperazine XXX is then reacted with formaldehyde and H3PO3, PCl3 or other H3PO3 source to produce N-(phosphonomethyl)glycine I and acetic acid. Acetic acid which is produced in the hydrolysis step can be reacted with ammonia to generate acetamide for the carboxymethylation step.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([F:10])[C:7]([OH:11])=[CH:6][C:5]=1[CH3:12])([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CC(C)=O>[N+:1]([C:4]1[CH:9]=[C:8]([F:10])[C:7]([O:11][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:6][C:5]=1[CH3:12])([O-:3])=[O:2]
Reactant: BrCc1ccccc1
Reactant: Cc1cc(O)c(F)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1cc(OCc2ccccc2)c(F)cc1[N+](=O)[O-]
Reaction time: 8 h

Procedure:
To a solution of 85.6 g 2-nitro-4-fluoro-5-hydroxy-toluene (0.5 mol) in 1300 ml acetone are added at room temperature 138 g K2CO3 (1.0 mol). 72 ml benzyl bromide (0.6 mol) are then added dropwise over 1 hour and the resulting mixture is stirred overnight at 60°. The solvent is evaporated and the residue taken up in AcOEt. The precipitate is removed by filtration and the solution is washed with water. The organic layer is dried over sodium sulfate, the solvent evaporated and the residue crystallized from hexane to yield 2-nitro-4-fluoro-5-benzyloxy-toluene. M.p.=95°.
Reaction SMILES: [F:1][C:2]1([F:25])[CH2:7][CH2:6][CH2:5][C:4]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:3]1.CCN(C(C)C)C(C)C.[CH3:35][N:36]([CH3:42])[C@@H:37]1[CH2:41][CH2:40][NH:39][CH2:38]1>>[F:1][C:2]1([F:25])[CH2:7][CH2:6][CH2:5][C:4]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:39]4[CH2:40][CH2:41][C@@H:37]([N:36]([CH3:42])[CH3:35])[CH2:38]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:3]1
Reactant: CN(C)[C@@H]1CCNC1
Reactant: O=C(NCC1(O)CCCC(F)(F)C1)c1c(Cl)ccc2nc(Cl)ccc12
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)[C@@H]1CCN(c2ccc3c(C(=O)NCC4(O)CCCC(F)(F)C4)c(Cl)ccc3n2)C1

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (3,3-difluoro-1-hydroxy-cyclohexylmethyl)-amide, DIPEA and (R)-3-dimethylamino-pyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.73 (m, 1H), 7.85 (1H), 7.48 (m, 2H), 6.69 (1H), 4.66 (s, 1H), 3.89 (m, 1H), 3.70 (m, 1H), 3.45 (m, 1H), 3.26 (m, 2H), 2.85 (m, 1H), 2.54 (m, 4H), 2.22 (s, 6H), 2.15 (m, 1H), 2.06 (m, 2H), 1.85 (m, 3H), 1.74-1.76 (m, 5H). m/z: 467 [M+H]
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:13]1([CH2:16][CH:17]([C:20]2[CH:21]=[N:22][C:23]([C:26]([F:29])([F:28])[F:27])=[N:24][CH:25]=2)[CH2:18][NH2:19])[CH2:15][CH2:14]1>>[Cl:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:19][CH2:18][CH:17]([C:20]1[CH:21]=[N:22][C:23]([C:26]([F:29])([F:28])[F:27])=[N:24][CH:25]=1)[CH2:16][CH:13]1[CH2:15][CH2:14]1)=[O:6]
Reactant: NCC(CC1CC1)c1cnc(C(F)(F)F)nc1
Reactant: COc1cccc(C(=O)O)c1Cl
Product: COc1cccc(C(=O)NCC(CC2CC2)c2cnc(C(F)(F)F)nc2)c1Cl

Procedure:
The racemic mixture which was prepared in a similar manner to example 3a from 2-chloro-3-methoxybenzoic acid and 3-cyclopropyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propan-1-amine was separated into the two enantiomers by preparative SFC to yield the title compound. LCMS (MH+): m/z=414.0, tR (minutes, Method F)=2.53. [α]D20=+26.3 (c=4.0 mg/mL,CHCl3)
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:11][CH2:10]2)[N:5]2[N:12]=[CH:13][C:14]([CH:15]=[O:16])=[C:4]2[N:3]=1.[N-:17]=[N+:18]=[N-:19].[Na+].O>CN(C)C=O>[N:17]([C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:11][CH2:10]2)[N:5]2[N:12]=[CH:13][C:14]([CH:15]=[O:16])=[C:4]2[N:3]=1)=[N+:18]=[N-:19]
Reactant: [N-]=[N+]=[N-]
Reactant: O=Cc1cnn2c(NC3CC3)cc(Cl)nc12
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=Nc1cc(NC2CC2)n2ncc(C=O)c2n1
Temperature: 80 °C
Yield: 71.9 %

Procedure:
To 5-chloro-7-(cyclopropylamino) pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (4.0 g, 16.87 mmol) in dimethylformamide was added sodium azide (1.56 g, 23.9 mmol) and the reaction mixture was heated at 80° C. for 8 hrs. Cooled the reaction mixture, added water and white precipitate filtered and dried to yield 5-azido-7-(cyclopropylamino) pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (2.95 g, 75% yield). LCMS (M+1=244)
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[N:13]=[CH:12][C:11]([CH:14]([OH:21])[CH2:15][NH:16][C@@H:17]([CH3:20])[CH2:18][OH:19])=[CH:10][CH:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.C(O[BH-](O[C:32](=O)[CH3:33])OC(=O)C)(=O)C.[Na+].[CH2:36](Cl)Cl>>[CH3:7][C:4]1[N:3]([C:8]2[N:13]=[CH:12][C:11]([CH:14]([OH:21])[CH2:15][N:16]([CH2:36][CH2:32][CH3:33])[C@@H:17]([CH3:20])[CH2:18][OH:19])=[CH:10][CH:9]=2)[C:2]([CH3:1])=[CH:6][CH:5]=1
Reactant: Cc1ccc(C)n1-c1ccc(C(O)CN[C@@H](C)CO)cn1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: ClCCl
Agent: [Na+]
Product: CCCN(CC(O)c1ccc(-n2c(C)ccc2C)nc1)[C@@H](C)CO
Temperature: 20 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
Propioanaldehyde (5.02 Kg, 86.4 mol) was added over 10 minutes to a solution of (2S)-2-[{(RS)-2-[6-(2,5-dimethyl-1H-pyrrol-1-yl)pyridin-3-yl]-2-hydroxyethyl} amino]propan-1-ol (22.7 Kg, 78.6 mol) in DCM (123 L) at 20° C. The resulting solution was stirred at 20° C. for 2 hours and then allowed to settle before adding it to a suspension of sodium triacetoxyborohydride (25.8 Kg, 122 mol) in DCM (123 L) over 90 minutes maintaining the temperature below 30° C. The reaction mixture was stirred at 20° C. for 1 hour before quenching with an aqueous solution of potassium carbonate (36.4 Kg in 136 L of water) and the phases were allowed to separate. The organic phase was washed with water (2×23 L). The equipment was set for distillation and DCM (190 L) was removed by distillation to give a final volume of 45 litres. The mixture was cooled to 20° C. Yield 100% (51.1 Kg, 50.9% w/w in DCM). δH (CDCl3, 300 MHz) 0.8-1.0 (6H, m), 1.50-1.70 (2H, m), 2.10 (6H, s), 2.50-3.15 (5H, m), 3.50 (2H, dd), 4.80 (1H, dd), 5.90 (2H, s), 7.20 (1H, m), 7.80-7.90 (1H, m), 8.60 (1H, m) ppm. MS m/z 332 (MH+).
Reaction SMILES: [C:1]([C@H:5]1[N:9]([CH3:10])[C:8](=[O:11])[CH2:7][N:6]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])([CH3:4])([CH3:3])[CH3:2].[Li+].[CH3:20]C([N-]C(C)C)C.C1COCC1.CCCCCCC.IC.[NH4+].[Cl-]>C1COCC1>[C:1]([C@H:5]1[N:9]([CH3:10])[C:8](=[O:11])[C@H:7]([CH3:20])[N:6]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)[N-]C(C)C
Reactant: CN1C(=O)CN(C(=O)OC(C)(C)C)[C@H]1C(C)(C)C
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CCCCCCC
Solvent: CI
Solvent: C1CCOC1
Product: C[C@H]1C(=O)N(C)[C@H](C(C)(C)C)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of (S)-tert-butyl 2-(tert-butyl)-3-methyl-4-oxoimidazolidine-1-carboxylate (0.5 g, 1.95 mmol; available from Aldrich#337595) in dry THF (15 ml) cooled to −78° C., LDA 2M in THF/heptane (0.97 ml, 1.95 mmol) was added and the reaction mixture stirred at this temperature for 40 min before adding iodomethane (0.146 ml, 2.34 mmol). The reaction was allowed to warm to RT and stirred for 18 hrs. The reaction mixture was cooled again at −78° C. then LDA 2M in THF/hepatane (0.3 ml) and iodomethane (0.04 ml, 0.6 mmol) were added in sequence. The mixture was allowed to reach RT and further stirred for 5 hrs. The resulting solution was treated with NH4Cl sat sol (5 ml) and extracted with Et2O. The organic phases were collected and washed with NaCl sat sol, dried over Na2SO4 and evaporated in vacuo to afford a residue which was purified by Biotage SNAP-Si column (25 g) eluting with cHex/Et2O 60/40. Collected fractions after solvent evaporation afforded the title compound (D43) (430 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[CH:5]([C:26]1[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=1)[CH2:6][C:7]1[NH:8][C:9]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[N:11]=1)C.IC.[C:36]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:1][O:3][C:4](=[O:33])[CH:5]([C:26]1[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=1)[CH2:6][C:7]1[N:8]([CH3:36])[C:9]([C:19]2[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=2)=[C:10]([C:12]2[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=2)[N:11]=1
Reactant: CCOC(=O)C(Cc1nc(-c2ccc(C)cc2)c(-c2ccc(C)cc2)[nH]1)c1cccc(C)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)C(Cc1nc(-c2ccc(C)cc2)c(-c2ccc(C)cc2)n1C)c1cccc(C)c1
Temperature: 40 °C
Yield: 26.9 %

Procedure:
A solution of 3-(4,5-di-p-tolyl-1H-imidazol-2-yl)-2-m-tolyl-propionic acid ethyl ester (Example 30, step C; 50 mg, 0.11 mmol), iodomethane (17 mg, 0.12 mmol) and K2CO3 (79 mg, 0.55 mmol) in DMF (2.0 mL) was stirred and heated to 40° C. overnight. The solvent was removed under reduced pressure, and the crude residue was purified on silica gel (EtOAc/CH2Cl2) to give 3-(1-methyl-4,5-di-p-tolyl-1H-imidazol-2-yl)-2-m-tolyl-propionic acid methyl ester (13 mg, 26%). The methyl ester (18 mg, 0.042 mmol) was hydrolyzed using the conditions outlined in Example 30, step D to provide the title compound (12 mg, 69% yield). HPLC: Rt=2.64 (Method A). MS (ESI): mass calculated for C28H28N2O2, 424.22; m/z found, 425.3 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.28-7.23 (m, 4H), 7.21-7.04 (m, 6H), 6.98 (d, J=7.8 Hz, 2H), 4.38 (d, J=9.3 Hz, 1H), 3.54 (dd, J=16.1, 9.3 Hz, 1H), 3.22 (dd, J=16.1, 3.1 Hz, 1H), 3.17 (s, 3H), 2.42 (s, 3H), 2.30 (s, 3H), 2.27 (s, 3H).