Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[C:13]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)[N:12]=2)[CH:10]=1)CCC.[C:39]([NH:43][S:44]([C:47]1[S:51][C:50](Cl)=[N:49][CH:48]=1)(=[O:46])=[O:45])([CH3:42])([CH3:41])[CH3:40].CCCCCCC>C1(C)C=CC=CC=1.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>[C:39]([NH:43][S:44]([C:47]1[S:51][C:50]([C:6]2[N:7]=[CH:8][N:9]([C:11]3[CH:16]=[C:15]([C:17]([F:20])([F:18])[F:19])[CH:14]=[C:13]([C:21]4[CH:22]=[CH:23][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:25][CH:26]=4)[N:12]=3)[CH:10]=2)=[N:49][CH:48]=1)(=[O:45])=[O:46])([CH3:42])([CH3:40])[CH3:41]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(-c2cc(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)n2)cn1
Reactant: CC(C)(C)NS(=O)(=O)c1cnc(Cl)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCCC
Solvent: Cc1ccccc1
Product: CC(C)(C)NS(=O)(=O)c1cnc(-c2cn(-c3cc(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)n3)cn2)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.7 %

Procedure:
A stirred mixture of 2-(4-tributylstannanyl-imidazol-1-yl)-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyridine (Example G.11) (0.575 g, 0.76 mmol), 2-chloro-thiazole-5-sulfonic acid tert-butylamide (Example H.1) (0.227 g, 0.85 mmol), tetrakis(triphenylphosphine)palladium (0.051 g, 0.038 mmol) in toluene (5 mL) was heated under reflux conditions for 4 h. Cooled to rt, some precipitate occurred, diluted with toluene (˜5 mL), placed in freezer for 30 min, added heptane (total volume: 25 mL), filtered the precipitate off, washed with toluene/heptane (ca. 1:1, 3×10 mL), dried in HV to give the title compound as an off-white solid (305 mg, 70%). MS (ISP) 576.3 [(M+H)+]; mp 236° C.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([CH2:32][CH2:33][CH3:34])[N:6]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[C:25]([C:30]#[N:31])=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:20][CH:19]=2)[C:7](=[O:16])[C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[CH3:2].I[CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>C(OCC)(=O)C>[CH3:36][C:37]([CH3:40])([CH3:39])[CH2:38][O:15][C:12]1[CH:11]=[CH:10][C:9]([C:8]2[C:7](=[O:16])[N:6]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[C:25]([C:30]#[N:31])=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:20][CH:19]=3)[C:5]([CH2:32][CH2:33][CH3:34])=[N:4][C:3]=2[CH2:1][CH3:2])=[CH:14][CH:13]=1
Reactant: CC(C)(C)CI
Reactant: CCCc1nc(CC)c(-c2ccc(O)cc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCc1nc(CC)c(-c2ccc(OCC(C)(C)C)cc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 80 °C
Reaction time: 12 h
Yield: 61.6 %

Procedure:
A mixture of 4′-{[4-ethyl-5-(4-hydroxyphenyl)-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile (0.52 g), 1-iodo-2,2-dimethylpropane (0.29 g), cesium carbonate (0.45 g) and dimethylformamide (10 mL) were stirred at 80° C. for 12 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.37 g, 62%).
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6]>C(O)C>[Cl:1][CH2:2][C@H:3]([OH:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)CC(=O)CCl
Solvent: CCO
Product: CCOC(=O)C[C@@H](O)CCl
Temperature: 120 °C
Reaction time: 3 h
Yield: 89.9 %

Procedure:
100 g of ethyl 4-chloro-3-oxobutyrate and 64.9 mg of {[Ru (p-cymene) I (+) TMBTP] I}, prepared in example 1, are placed under argon in a 3-liter reactor, in 1000 ml of ethyl alcohol degassed with argon; the mixture is heated at 120° C. under argon and pressurised with hydrogen at 5 bar. After 3 h, the mixture is cooled, concentrated at reduced pressure, and the residue distilled with 5 mm Hg vacuum. 91 g of ethyl (+) (R)-4-chloro-3-hydroxybutyrate are obtained with an e.e. of 97% by gas-chromatography analysis.
Reaction SMILES: NC1C=CC(OC2C=C3C(=CC=2)OC(C2C=CC=CC=2)CC3)=NC=1.[F:25][C:26]([F:54])([F:53])[C:27]1[CH:32]=[CH:31][C:30]([CH:33]2[CH2:42][CH2:41][C:40]3[C:35](=[CH:36][CH:37]=[C:38]([O:43][C:44]4[CH:49]=[CH:48][C:47]([N+:50]([O-])=O)=[CH:46][N:45]=4)[CH:39]=3)[O:34]2)=[CH:29][CH:28]=1>>[F:54][C:26]([F:25])([F:53])[C:27]1[CH:32]=[CH:31][C:30]([CH:33]2[CH2:42][CH2:41][C:40]3[C:35](=[CH:36][CH:37]=[C:38]([O:43][C:44]4[N:45]=[CH:46][C:47]([NH2:50])=[CH:48][CH:49]=4)[CH:39]=3)[O:34]2)=[CH:29][CH:28]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccc(C(F)(F)F)cc2)O3)nc1
Agent: Nc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Product: Nc1ccc(Oc2ccc3c(c2)CCC(c2ccc(C(F)(F)F)cc2)O3)nc1

Procedure:
6-[2-(4-Trifluoromethylphenyl)chroman-6-yloxy]pyridin-3-ylamine was prepared as described for 5-amino-2-(2-phenylchroman-6-yloxy)pyridine in Example 26 starting from 275 mg of 2-[2-(4-trifluoromethylphenyl)chroman-6-yloxy]-5-nitropyridine (Example 64(d)). 1H NMR (400 MHz, d6-DMSO) δ: 7.78 (d, 2H, J 8.4 Hz), 7.68 (d, 2H, J 8.4 Hz), 7.52 (dd, 1H, J 2.9, 0.5 Hz), 7.06 (dd, 1H, 8.6, 2.9 Hz) 6.84 (m, 1H), 6.77-6.75 (m, 2H), 6.70 (dd, 1H, J 8.6, 0.5 Hz), 5.23 (dd, 1H, J 10.0, 2.0 Hz), 5.01 (s, 2H), 2.95 (ddd, 1H, −16.8, 11.1, 5.9 Hz), 2.69 (ddd, 1H, J −16.8, 8.5, 4.8 Hz), 2.21 (m, 1H), 1.97 (m, 1H).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C@H:7]1[CH2:11][CH2:10][NH:9][CH2:8]1.Cl[C:13]1[N:18]=[CH:17][C:16]([N:19]2[CH2:23][CH2:22][C:21]3([CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:20]2=[O:29])=[CH:15][N:14]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C@H:7]1[CH2:11][CH2:10][N:9]([C:13]2[N:14]=[CH:15][C:16]([N:19]3[CH2:23][CH2:22][C:21]4([CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[C:20]3=[O:29])=[CH:17][N:18]=2)[CH2:8]1
Reactant: O=C1N(c2cnc(Cl)nc2)CCC12CCOCC2
Reactant: C[C@H]1CCCN1[C@H]1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@H]1CCCN1[C@H]1CCN(c2ncc(N3CCC4(CCOCC4)C3=O)cn2)C1
Temperature: 70 °C
Reaction time: 16 h
Yield: 72.5 %

Procedure:
To a solution of (2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl (0.072 g, 0.315 mmol) in acetonitrile (25 mL) was added 2-(2-chloro-pyrimidin-5-yl)-8-oxa-2-aza-spiro[4.5]decan-1-one (0.07 g, 0.262 mmol), and powdered potassium carbonate (0.145 g, 1.05 mmol) and stirred at 70° C. for 16.0 hours. Additional (2S,3′S)-2-Methyl-[1,3′]bipyrrolidinyl (0.1 g) was added and reaction mixture stirred for 4 hours at 70° C. The reaction mixture was then allowed to cool to room temperature, quenched with water (2 mL) diluted with ethyl acetate (10 mL). The aqueous phase was extracted with 10% methanol in dichloromethane (10 ml, 3×), combined organics washed with brine, dried over Na2SO4, concentrated under vacuum. Purification by column chromatography on silica gel (0-100%) eluting with methanol in dichloromethane (0-10%) afforded 0.0732 g (72%) of the title compound.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][NH:6][C:7]([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH2:16][CH2:17][NH:18][CH2:19][CH:20]=3)=[N:13][CH:14]=2)=[O:8])[CH2:3][CH2:2]1.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26].C(N(CC)CC)C>ClCCl>[CH:1]1([CH2:4][CH2:5][NH:6][C:7]([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH2:16][CH2:17][N:18]([C:25](=[O:26])[C:24]4[CH:28]=[CH:29][CH:30]=[CH:31][C:23]=4[C:22]([F:21])([F:32])[F:33])[CH2:19][CH:20]=3)=[N:13][CH:14]=2)=[O:8])[CH2:3][CH2:2]1
Reactant: O=C(NCCC1CC1)c1ccc(C2=CCNCC2)nc1
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCC1CC1)c1ccc(C2=CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42 %

Procedure:
To a stirred solution of 1′,2′,3′,6′-tetrahydro[2,4′]bipyridinyl-5-carboxylic acid (2-cyclopropylethyl)amide (0.050 g, 0.184 mmol) in dichloromethane (5.0 mL) was added 2-(trifluoromethyl)benzoyl chloride (32 μL, 0.203 mmol), and triethylamine (31 μL, 0.203 mmol). The resulting mixture was stirred at room temperature for 30 minutes. The organic phase was washed with water (5 mL), saturated NaCl (5 mL), dried over MgSO4 and then concentrated in vacuo. The crude product was purified by column chromatography to afford the pure title compound in 42% yield (0.453 g). 1H NMR (300 MHz, CDCl3) δ 8.88 (s, 1H), 8.09 (d, J=8.3 Hz, 1H), 7.73-7.67 (m, 1H), 7.63-7.51 (m, 3H), 7.46-7.41 (m, 1H), 7.38-7.32 (m, 1H), 6.77 (s, 1H), 6.49-6.43 (m, 1H), 4.70-4.43 (m, 1H), 4.33-4.26 (m, 1H), 4.15-4.06 (m, 1H), 3.96-3.88 (m, 1H), 3.56-3.49 (dd, J=6.7 and 6.3 Hz, 2H), 3.47-3.30 (m, 2H), 2.76-2.60 (m, 2H), 1.54-1.47 (dd, J=6.8 and 7.0 Hz, 2H), 0.74-0.66 (m, 1H), 0.49-0.44 (m, 2H), 0.10-0.045 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 167.7, 165.3, 158.8, 147.2, 135.6, 134.7, 132.3, 129.3, 128.6, 127.2, 127.1, 125.4, 124.3, 118.6, 60.4, 47.1, 43.9, 42.3, 40.4, 34.3, 25.9, 8.6, 4.2. MS (ES+) m/z 444.0 (M+1).
Reaction SMILES: [C:1]([C:4](=[CH:10][CH2:11][CH:12]([CH3:14])[CH3:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6])(=[O:3])[CH3:2].BrN1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[CH:12]([C:11]1[O:3][C:1]([CH3:2])=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:10]=1)([CH3:13])[CH3:14]
Reactant: CCOC(=O)C(=CCC(C)C)C(C)=O
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1cc(C(C)C)oc1C
Yield: 84.8 %

Procedure:
A mixture of 3.97 g (0.02 mole) ethyl 2-acetyl-5-methyl-2-hexenoate and 3.55 g (0.02 mole) N-bromosuccinimide in 50 ml of carbon tetrachloride was heated at reflux for 2.5 hours. After cooling, the succinimide was removed by filtration and the solution concentrated by rotary evaporation. Distillation of the crude product gave 3.33 g (85% ) of ethyl 5-isopropyl-2-methyl-3-furoate, bp 112°-114° C. (11 mm).
Reaction SMILES: [F:1][C@H:2]1[C@@H:7]([CH2:8]C(O)=O)[CH2:6][CH2:5][N:4]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)=[O:13])[CH2:3]1.C([N:25](CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[OH-].[Na+]>C1(C)C=CC=CC=1.O1CCOCC1>[NH2:25][CH2:8][C@H:7]1[CH2:6][CH2:5][N:4]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)=[O:13])[CH2:3][C@H:2]1[F:1]
Reactant: Cc1ccc(COC(=O)N2CC[C@H](CC(=O)O)[C@H](F)C2)cc1
Reactant: CCN(CC)CC
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: Cc1ccc(COC(=O)N2CC[C@H](CN)[C@H](F)C2)cc1
Temperature: 70 °C
Reaction time: 0.33 h
Yield: 91 %

Procedure:
To a suspension of crude acid (±)-((cis)-3-fluoro-1-{[(4-methylbenzyl)oxy]carbonyl}piperidin-4-yl)acetic acid (9.1 g, 29.4 mmol) in toluene (80 mL) was added triethylamine (10.2 mL, 73.5 mmol) and diphenylphosphoryl azide (9.52 mL, 44.1 mmol). The reaction mixture was heated to 70° C. and stirred for 20 min. A mixture of dioxane (80 mL) and 1 M NaOH (80 mL) was added and the reaction mixture was cooled to RT. The reaction mixture was concentrated to remove the dioxane and extracted with EtOAc three times, dried over Na2SO4, filtered and concentrated. The residue was suspended in CH2Cl2, stirred for 30 min, and the white preciptate filtered off. The filtrate was concentrated to give crude product (7.5 g) as a yellow oil, used directly in the next step. An analytical sample was purified by silica gel chromatography (gradient elution: CH2Cl2 to 80:20:2 CH2Cl2:MeOH:NH4OH) for characterization:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]1([CH3:19])[CH3:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=C[NH+]=CC=1.[O-:26][Cr](Cl)(=O)=O>C1COCC1.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:26])[CH2:10][C:9]1([CH3:19])[CH3:18])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1c2ccccc2C=CC1(C)C
Reactant: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1c2ccccc2C(=O)CC1(C)C
Reaction time: 1 h
Yield: 19.1 %

Procedure:
A solution of aniline (19 mL, 0.20 mol), 3-acetoxy-3-methyl-1-butyne (26 g, 0.20 mol), CuCl (1.0 g, 10 mmol) and Et3N (28 mL, 0.20 mol) in THF (120 mL) was heated at reflux for 5 h and was filtered through a pad of Celite™. Removal of solvent and chromatography of the crude mixture (silica gel, EtOAc/hexane, 3/7) afforded 21 g (67%) of 3-methyl-3-phenylamino-1-butyne. Treatment of the aminobutyne with CuCl (0.70 mg, 7.0 mmol) in THF (200 mL) at 70° C. for 16 h followed by chromatography (silica gel, EtOAc/hexane, 3/7) afforded 13 g (60%) of 1,2-dihydro-2,2-dimethylquinoline (structure 75A of Scheme LII, where R1 =H, R2-3 =methyl). Treatment of the quinoline with di-tert-butyl dicarbonate (22 g, 0.10 mol) and DMAP (12 g, 0.10 mol) in THF (100 mL) for 16 h followed by chromatography (silica gel, EtOAc/hexane, 2/8) afforded 15 g (71%) of 1-tert-butoxycarbonyl-1,2-dihydro-2,2-dimethylquinoline. 1-tert-Butoxycarbonyl-1,2-dihydro-2,2-dimethylquinoline (3.0 g, 11 mmol) in THF (30 mL) was treated with 1.0M BH3 -THF in THF (29 mL, 29 mmol) at rt for 3 h and was quenched with 3M KOH (20 mL). To the above solution 30% H2O2 (5 mL) was added and the mixture was stirred for 60 min, then 5 mL of water was introduced. The mixture was extracted, washed with brine and concentrated. Chromatography of the crude mixture on a silica gel column using a 10-30% mixture of EtOAc/Hexane as eluents afforded a 2:1 mixture of two isomers (0.87 g, 3.1 mmol), which was oxidized with PCC (2.5 g, 11 mmol) in 60 mL of methylene chloride at rt for 60 min. Removal of solvent and chromatography of the black oil on a silica gel column using a 20% mixture of EtOAc and hexane as solvent afforded 0.58 g (68%) of 1-tert-butoxycarbonyl-1,2,3,4-tetrahydro-2,2-dimethyl-4-quinolinone as a white solid. Data for 1-tert-butoxycarbonyl-1,2,3,4-tetrahydro-2,2-dimethyl-4-quinolinone: 1H NMR (400 MHz, CDCl3) 7.93 (d, J=7.8, 1 H), 7.42 (t, J=7.8, 1 H), 7.31 (d, J=7.8, 1 H), 7.02 (t, J=7.8, 1 H), 2.73 (s, 2 H), 1.56 (s, 9 H), 1.49 (s, 6 H).
Reaction SMILES: CC(=O)CC(=O)C.NC1C(C(OCC)=O)=CNN=1.[CH3:19][C:20]1[CH:25]=[C:24]([CH3:26])[N:23]2[N:27]=[CH:28][C:29]([C:30]([O:32]CC)=[O:31])=[C:22]2[N:21]=1.[OH-].[Na+]>CO.C(OCC)C.C(O)(=O)C>[CH3:19][C:20]1[CH:25]=[C:24]([CH3:26])[N:23]2[N:27]=[CH:28][C:29]([C:30]([OH:32])=[O:31])=[C:22]2[N:21]=1
Reactant: CCOC(=O)c1cnn2c(C)cc(C)nc12
Agent: CCOC(=O)c1c[nH]nc1N
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: CC(=O)CC(C)=O
Product: Cc1cc(C)n2ncc(C(=O)O)c2n1
Temperature: 75 °C
Reaction time: 3 h
Yield: 56.6 %

Procedure:
Pentane-2,4-dione (1.46 ml, 14.2 mmol), ethyl 3-amino-1H-pyrazole-4-carboxylate (2.00 g, 12.9 mmol) were heated in a sealed tube with acetic acid (10 ml) at 110° C. overnight. The reaction reached completion by LCMS (LC-MS: rt (min)=3.08). The acetic acid was removed by blowing air with the flask being heated to 75° C. The crude residue of ethyl 5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxylate (assumed to be 12.89 mmol) was suspended in MeOH (15 ml) and treated with 7.2 M sodium hydroxide (5.37 ml, 38.7 mmol). The mixture was heated to 80° C. (at this temperature the solid dissolved) and then stirred for 3 h. The reaction was cooled and the neutralized to pH 6-7. The slurry was filtered via a Büchner funnel under house vacuum, the solid residue was washed with water and then diethyl ether to obtain 5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (1.4 g, 7.3 mmol, 57% yield). LC-MS: rt (min)=2.61. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.57 (s, 3H), 2.71 (s, 3H), 7.10 (s, 1H), 8.50 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].Br[C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=1.CC(C)([O-])C.[Na+].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([O:5][C:6](=[O:15])[NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCC1CCCNC1
Reactant: FC(F)(F)c1ccc(Br)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NCC1CCCN(c2ccc(C(F)(F)F)cc2)C1
Temperature: 120 °C
Yield: 89.6 %

Procedure:
A solution of piperidin-3-ylmethyl-carbamic acid tert-butyl ester (1.00 g, 4.67 mmol), 1-bromo-4-trifluoromethyl-benzene (1.15 g, 5.13 mmol), sodium tert-butoxide (673 mg, 7.00 mmol), (R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (291 mg, 0.47 mmol) and tris(dibenzylideneacetone)-dipalladium (0) (214 mg, 0.23 mmol) in toluene (5 mL) at 25° C. was purged with nitrogen gas and evacuated three times. The solution was sealed and heated to 120° C. for 14 h. The reaction mixture was cooled to 25° C., unsealed and poured into water. The aqueous phase was extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over magnesium sulfate. Filtration followed by concentration in vacuo to afford crude [1-(4-trifluoromethyl-phenyl)-piperidin-3-ylmethyl]-carbamic acid tert-butyl ester (1.5 g, 90% crude) as a light oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@@:9]([OH:21])([CH2:15][N:16]1[CH:20]=[N:19][CH:18]=[N:17]1)[C@@H:10]([CH3:14])[C:11]([NH2:13])=O.O=P(Cl)(Cl)Cl>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@@:9]([OH:21])([CH2:15][N:16]1[CH:20]=[N:19][CH:18]=[N:17]1)[C@H:10]([CH3:14])[C:11]#[N:13]
Reactant: C[C@@H](C(N)=O)[C@](O)(Cn1cncn1)c1cc(F)ccc1F
Solvent: O=P(Cl)(Cl)Cl
Product: C[C@H](C#N)[C@](O)(Cn1cncn1)c1cc(F)ccc1F
Yield: 185.1 %

Procedure:
5.8 g (20 mmol) of (2R,3R)-3-(2,5-difluoro-phenyl)-3-hydroxy-2-methyl-4-[1,2,4]triazol-1-yl-butyramide were heated with 7.3 ml (78 mmol) of POCl3 at 40° C. for 3 hours. After cooling to room temperature the excess POCl3 was evaporated at reduced pressure to yield crude 10.3 g of (2R,3R)-3-(2,5-difluorophenyl)-3-hydroxy-2-methyl-4-[1,2,4]triazol-1-yl-butyronitrile which was used directly in the next step (Example 14).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([NH:17][O:18]C)=[O:16])=[C:11]([F:20])[CH:10]=2)[CH2:4]1.C(N(CC)CC)C.[C:28](SCC)(=[S:30])[CH3:29]>CN(C=O)C>[C:28]([NH:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([NH:17][OH:18])=[O:16])=[C:11]([F:20])[CH:10]=2)[CH2:4]1)(=[S:30])[CH3:29]
Reactant: CCSC(C)=S
Reactant: CONC(=O)c1ccc(N2C[C@H](CN)OC2=O)cc1F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=S)NC[C@H]1CN(c2ccc(C(=O)NO)c(F)c2)C(=O)O1

Procedure:
A solution of 5-(S)-aminomethyl-3-[4′-(N-methoxyamino)carbonyl-3′-fluorophenyl]-oxazolidine-2-one (0.053 ml, 0.47 mmol), triethylamine (0.12 ml, 0.84 mmol) and ethyl dithioacetate (0.87 ml, 7.6 mmol) in DMF (0.75 ml) was stirred at r.t. for 48 h. Solvent was removed under vacuum, and the crude material purified by silica gel PTLC (eluent: 5% MeOH in ethyl acetate). White crystalline solid (100 mg, 70%). HPLC Rt=4.6 min. MS (m/z): [M+H]+=342.
Reaction SMILES: [C:1]12([CH:11]([NH:16][C:17]3[C:22]([F:23])=[CH:21][N:20]=[C:19]([C:24]4[C:32]5[C:27](=[N:28][CH:29]=[C:30](F)[CH:31]=5)[NH:26][CH:25]=4)[N:18]=3)[CH2:12][C:13]([OH:15])=[O:14])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[Cl:34]C1C=C2C(B3OC(C)(C)C(C)(C)O3)=CN(S(C3C=CC(C)=CC=3)(=O)=O)C2=NC=1.FC1C=C2C(B3OC(C)(C)C(C)(C)O3)=CN(S(C3C=CC(C)=CC=3)(=O)=O)C2=NC=1.C(O)=O>C(#N)C>[C:1]12([CH:11]([NH:16][C:17]3[C:22]([F:23])=[CH:21][N:20]=[C:19]([C:24]4[C:32]5[C:27](=[N:28][CH:29]=[C:30]([Cl:34])[CH:31]=5)[NH:26][CH:25]=4)[N:18]=3)[CH2:12][C:13]([OH:15])=[O:14])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(Cl)cnc32)cc1
Reactant: O=C(O)CC(Nc1nc(-c2c[nH]c3ncc(F)cc23)ncc1F)C12CC3CC(CC(C3)C1)C2
Agent: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(F)cnc32)cc1
Solvent: CC#N
Solvent: O=CO
Product: O=C(O)CC(Nc1nc(-c2c[nH]c3ncc(Cl)cc23)ncc1F)C12CC3CC(CC(C3)C1)C2

Procedure:
Compound 94 was synthesized in a manner similar to 3-(1-Adamantyl)-3-[[5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl]amino]propionic acid, 86, using 5-chloro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine instead of boronate ester, 7a: 1H NMR (400 MHz, CD3OD) δ 9.02 (d, J=2.3 Hz, 1H), 8.40-8.24 (m, 2H), 8.18 (d, J=5.0 Hz, 1H), 4.91 (d, J=11.6 Hz, 1H), 2.88 (dd, J=16.0, 2.8 Hz, 1H), 2.65 (dd, J=15.9, 11.0 Hz, 1H), 2.01 (s, 3H), 1.77 (dd, J=27.9, 11.9 Hz, 12H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time=2.60 minutes (M+H) 470.27.
Reaction SMILES: [ClH:1].[CH:2]1([N:14]2[CH2:30][CH2:29][C:17]3([N:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:20][NH:19][C:18]3=[O:28])[CH2:16][CH2:15]2)[C:12]2=[C:13]3[C:8](=[CH:9][CH:10]=[CH:11]2)[CH:7]=[CH:6][CH:5]=[C:4]3[CH2:3]1.[CH3:31]I>>[ClH:1].[CH:2]1([N:14]2[CH2:15][CH2:16][C:17]3([N:21]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:20][N:19]([CH3:31])[C:18]3=[O:28])[CH2:29][CH2:30]2)[C:12]2=[C:13]3[C:8](=[CH:9][CH:10]=[CH:11]2)[CH:7]=[CH:6][CH:5]=[C:4]3[CH2:3]1
Reactant: O=C1NCN(c2ccccc2)C12CCN(C1Cc3cccc4cccc1c34)CC2
Reactant: CI
Agent: Cl
Product: CN1CN(c2ccccc2)C2(CCN(C3Cc4cccc5cccc3c45)CC2)C1=O

Procedure:
The title compound, light brown solid, m.p.>185° C. (dec.) and MS: m/e=398.3 (M+H+) was prepared in accordance with the general method of example 4 from (RS)-8-(acenaphthen-1-yl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one hydrochloride (1:1) and methyl iodide.
Reaction SMILES: [CH2:1]([N:3]([CH2:29][CH3:30])[C:4](=O)[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2[N:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)=[CH:16][N:15]=2)=[CH:9][CH:8]=1)[CH3:2].[Li].C1COCC1>CO>[CH2:29]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:14]2[N:15]=[CH:16][C:17]([C:20]3[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=3)=[CH:18][N:19]=2)=[CH:11][CH:12]=1)[CH3:30]
Reactant: CCN(CC)C(=O)CCc1ccc(Nc2ncc(-c3ccc(OC)cc3)cn2)cc1
Agent: [Li]
Solvent: CO
Solvent: C1CCOC1
Product: CCN(CC)CCCc1ccc(Nc2ncc(-c3ccc(OC)cc3)cn2)cc1

Procedure:
N,N-Diethyl-3-{4-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]-phenyl}-propionamide (0.1 mmol) is heated at reflux with lithium alluminium hydride in THF (1.0 M, 1.0 mmol) for 4 h. MeOH is added at rt to quench the reaction. Purification by preparative LCMS affords the title compound. 1H NMR (400 MHz, CDCl3) δ 12.4 (s, 1H), 8.62 (s, 2H), 8.59 (s, 1H), 7.61 (d, J=8.3 Hz, 2H), 7.43 (d, J=8.6 Hz, 2H), 7.17 (d, J=8.2 Hz, 2H), 7.02 (d, J=8.6 Hz, 2H), 3.86 (s, 3H), 3.1 (m, 4H), 3.96 (s, 1H), 3.0 (m, 2H), 2.71 (t, J=7.2, 2H), 2.06 (m, 2H), 1.27 (t, J=7.3 Hz, 6H). MS (m/z) (M+1)+ 391.2.
Reaction SMILES: [Br:1][C:2]1[C:7]2[C:8](=[O:19])[N:9]([CH3:18])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]#[N:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl.[NH2:27][OH:28]>C(O)C.O>[Br:1][C:2]1[C:7]2[C:8](=[O:19])[N:9]([CH3:18])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16](=[N:27][OH:28])[NH2:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: CN1Cc2c(C#N)ncn2-c2cccc(Br)c2C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CN1Cc2c(C(N)=NO)ncn2-c2cccc(Br)c2C1=O
Yield: 86 %

Procedure:
17.85 g (56.3 mmol) of 7-bromo-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carbonitrile were stirred with 10.3 g (97.7 mmol) of sodium carbonate and 8 g (115.1 mmol) of hydroxylamine hydrochloride in 300 ml of ethanol and 60 ml of water at 50° for 1 hour and at 75° for 20 minutes. After dilution with 50 ml of water the suspension was suction filtered and the crystals were dried. There were obtained 16.95 g (86%) of 7-bromo-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamidoxime of m.p. 265°-266°.