Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:28][C:29](=[O:37])[CH2:30][CH2:31][CH:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:16][CH2:15][C@H:14]([NH:17][CH2:18][CH2:19][O:20][Si](C(C)(C)C)(C)C)[CH2:13]1)[CH:6]=[CH:5]2.Cl>ClCCl.CO>[Cl:1][C:2]1[C:3]([NH:28][C:29](=[O:37])[CH2:30][CH2:31][CH:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:16][CH2:15][C@H:14]([NH:17][CH2:18][CH2:19][OH:20])[CH2:13]1)[CH:6]=[CH:5]2
Reactant: CC(C)(C)[Si](C)(C)OCCN[C@H]1CCN(c2ccc3c(NC(=O)CCC4CCCC4)c(Cl)ccc3n2)C1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: O=C(CCC1CCCC1)Nc1c(Cl)ccc2nc(N3CC[C@H](NCCO)C3)ccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 22.1 %

Procedure:
To a stirred solution of N-[6-chloro-2-[(3S)-3-[[2-[[(1,1-dimethylethyl)dimethylsilyl]oxy]ethyl]amino]-1-pyrrolidinyl]-5-quinolinyl]-cyclopentanepropanamide (Example 63(a)) (200 mg) in dichloromethane:methanol 1:1 (3 mL) under nitrogen, was added HCl (1 mL, 4M solution in dioxane). The reaction mixture was stirred at room temperature for 30 minutes, then evaporated to dryness. Purification (HPLC, Symmetry—0.1% aqueous trifluoroacetic acid/acetonitrile) gave the title compound as a solid (35 mg).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:68])[C@H:10]([CH2:62][CH:63]1[CH2:67][CH2:66][CH2:65][CH2:64]1)[NH:11]C(=O)[C@H](C(C)(C)C)NC(=O)[C@H](CC1C=CC=CC=1C)NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>N1CCCCC1.ClCCl>[CH2:1]([O:8][C:9](=[O:68])[C@H:10]([CH2:62][CH:63]1[CH2:64][CH2:65][CH2:66][CH2:67]1)[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccccc1C[C@H](NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N[C@H](C(=O)N[C@@H](CC1CCCC1)C(=O)OCc1ccccc1)C(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: C1CCNCC1
Product: N[C@@H](CC1CCCC1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 520 mg (0.56 mmol) of N-[N-[N-[O-tert-butyl-N-[(9-fluorenyl)methoxycarbonyl]-L-a-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-3-cyclopentyl-L-alanine benzyl ester in 3 ml of piperidine and 12 ml of dichloromethane was stirred at room temperature for 30 minutes. The solvent was removed by evaporation and the residue was chromatographed on silica gel using firstly ethyl acetate/petrol (1:1) and then methanol/dichloromethane (1:9) for the elution. The resulting amine was added to a solution of 207 mg (0.504 mmol) of N-(9-fluorenyl-methoxycarbonyl)-O-tert-butyl-L-α-aspartic acid, 78 mg (0.51 mmol) of 1-hydroxybenzotriazole and 134 mg (0.7 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in 10 ml of dichloromethane and stirred at room temperature for 18 hours. The solution was then extracted with 2M hydrochloric acid and saturated sodium bicarbonate solution and dried over anhydrous magnesium sulphate. Evaporation, trituration with diethyl ether and filtration gave 440 mg of N-[N-[N-[N-O-tert-butyl-N-[(9-fluorenyl)methoxycarbonyl]-L-a-aspartyl]-O-tert-butyl-L-α-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-3-cyclopentyl-L-alanine benzyl ester as a white solid; MS: m/e 1101 [M+H].
Reaction SMILES: C[O:2][C:3]([C:5]1[O:6][C:7]([CH3:19])=[C:8]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=2)[CH:9]=1)=[O:4].[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=1B(O)O>>[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=1[C:15]1[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:8]2[CH:9]=[C:5]([C:3]([OH:2])=[O:4])[O:6][C:7]=2[CH3:19])=[CH:13][CH:14]=1
Reactant: COC(=O)c1cc(COc2ccc(I)cc2)c(C)o1
Reactant: OB(O)c1c(F)cccc1F
Product: Cc1oc(C(=O)O)cc1COc1ccc(-c2c(F)cccc2F)cc1

Procedure:
Compound (100) was prepared from compound (20) and (2,6-difluorophenyl)-boronic acid by adapting the procedure of Example 5(b). LC/MS System B; Rt=1.83 mins, m/z (ES−) 343 (M−H for C19H14F2O4).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:16]=4[C:15](=[O:23])[N:14]([CH3:24])[CH2:13][C:12]=23)[S:6][CH:7]=1.[CH2:25]([NH:28][CH2:29][CH2:30][CH3:31])[CH2:26][CH3:27]>O1CCCC1>[CH2:25]([N:28]([CH2:2][C:3]1[N:4]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:16]=4[C:15](=[O:23])[N:14]([CH3:24])[CH2:13][C:12]=23)[S:6][CH:7]=1)[CH2:29][CH2:30][CH3:31])[CH2:26][CH3:27]
Reactant: CCCNCCC
Reactant: CN1Cc2c(-c3nc(CCl)cs3)ncn2-c2ccc(F)cc2C1=O
Solvent: C1CCOC1
Product: CCCN(CCC)Cc1csc(-c2ncn3c2CN(C)C(=O)c2cc(F)ccc2-3)n1
Reaction time: 12 h
Yield: 28.9 %

Procedure:
A suspension of 1.0 g (0.00275 mol) of 3-(4-chloromethylthiazol-2-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one in 50 ml of tetrahydrofuran was treated with 4.5 ml (0.033 mol) of dipropylamine. After stirring at 50° for 12 hrs. the solution obtained was completely freed from the solvents. The residue was chromatographed over silica gel with dichloromethane/methanol 19:1 as the eluent and recrystallized from hot isopropyl ether. There was obtained 0.34 g (29%) of 3-(4-dipropylaminomethyl-thiazol-2-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one as white crystals; m.p.134°-136°.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7](Cl)=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1)=[O:3].[CH3:14][CH:15]([CH3:19])[CH2:16][CH2:17][NH2:18]>>[CH3:14][CH:15]([CH3:19])[CH2:16][CH2:17][NH:18][C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH3:1])=[CH:5][C:6]=1[N+:11]([O-:13])=[O:12]
Reactant: CC(C)CCN
Reactant: CC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Product: CC(=O)c1ccc(NCCC(C)C)c([N+](=O)[O-])c1

Procedure:
4-chloro-3-nitroacetophenone was treated with 3-methylbutyl amine to give 1-[4-(3-methyl-butylamino)-3-nitro-phenyl]-ethanone, compound 282.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][N:4]=1)#[N:2].[CH3:10]N(C=O)C.C([O-])([O-])=O.[K+].[K+].CI>O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][N:4]=1)#[N:2]
Reactant: CN(C)C=O
Reactant: N#Cc1ccc(O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Product: COc1ccc(C#N)nc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 78 %

Procedure:
2-Cyano-5-hydroxy pyridine (200 mg, 1.66 mmol), DMF (10 mL) and K2CO3 (253 mg, 1.83 mmol), and MeI (354 mg, 2.49 mmol) were combined at rt and the reaction mixture was stirred for 24 h at rt. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was separated, washed with water, dried and concentrated to give 2-cyano-5-methoxy pyridine (175 mg, 78%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([NH2:15])=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1.[C:16]([O:20][C:21]([NH:23][C@@H:24]([CH3:28])[C:25](O)=O)=[O:22])([CH3:19])([CH3:18])[CH3:17].C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:16]([O:20][C:21](=[O:22])[NH:23][C@H:24]([C:25]1[N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:14]2[N:15]=1)[CH3:28])([CH3:19])([CH3:18])[CH3:17]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nc1cccnc1Nc1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: C[C@H](NC(=O)OC(C)(C)C)c1nc2cccnc2n1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.2 %

Procedure:
A mixture of N2-(4-chlorophenyl)pyridine-2,3-diamine (64 mg, 0.291 mmol), (S)-2-tertbutoxycarbonylaminopropionic acid (61 mg, 0.32 mmol), HOAt (44 mg, 0.32 mmol), 4-methylmorpholine (70 μL, 0.641 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (61 mg, 0.32 mmol) in DCM (10 mL) was stirred at RT for 1 h then left standing at RT for 64 h. The reaction mixture was partitioned between DCM and a saturated aqueous solution of NaHCO3. The organic fraction was washed with brine, dried and concentrated in vacuo. The resulting {(S)-1-[2-(4-chlorophenylamino)pyridin-3-ylcarbamoyl]ethyl}carbamic acid tert-butyl ester, as a brown oil (136 mg), was dissolved in AcOH (5 mL) and heated at 70° C. for 4 h. After cooling to RT, the volatiles were removed under reduced pressure. The resulting residue was partitioned between EtOAc and a saturated aqueous solution of NaHCO3. The organic fraction was washed with water, followed by brine, dried (Na2SO4) and concentrated in vacuo. The resulting brown oil was purified by column chromatography (Si—PCC, gradient 0-5% MeOH in DCM) to afford the title compound as an orange/brown oil (99 mg, 91% over two steps). LCMS (Method C): RT 3.33 min [M+H]+ 373.2.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)=[N:5][C:6]([NH2:12])=[N:7][C:8]=1[S:9]([CH3:11])=O)[CH3:2].[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24]CS.C1CCN2C(=NCCC2)CC1>COCCOC>[CH2:1]([C:3]1[C:4]([C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)=[N:5][C:6]([NH2:12])=[N:7][C:8]=1[S:9][CH2:11][CH2:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=1)[CH3:2]
Reactant: SCCc1ccccn1
Reactant: CCc1c(-c2ccco2)nc(N)nc1S(C)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: CCc1c(SCCc2ccccn2)nc(N)nc1-c1ccco1
Temperature: 90 °C
Yield: 19.1 %

Procedure:
To a stirred suspension of 100 mg (0.40 mmol) 5-ethyl-4-furan-2-yl-6-methanesulfinyl-pyrimidin-2-ylamine in 5 ml DME in a pressure tube were added 230 mg (1.65 mmol) 2-pyridylethyl mercaptan and 0.18 ml (1.19 mmol) DBU and the mixture heated at 90° C. for 16 hours. The reaction mixture was then concentrated in vacuo. Chromatography (ethyl acetate/hexane 1/1 then ethyl acetate) followed by trituration in ether afforded 25 mg (19%) 5-ethyl-4-furan-2-yl-6-(2-pyridin-2-yl-ethylsulfanyl)-pyrimidin-2-ylamine as a beige crystalline solid. ES-MS m/e (%): 327 (M+H+, 100).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:15])[C:5]([N+:12]([O-])=O)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C(O)(=O)C>CO.[Pd]>[NH2:12][C:5]1[C:4]([OH:15])=[CH:3][C:2]([F:1])=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(F)cc(O)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1cc(F)cc(O)c1N
Reaction time: 1.5 h
Yield: 80.9 %

Procedure:
To a solution of methyl 5-fluoro-3-hydroxy-2-nitrobenzoate (1.15 g, 5.34 mmol) in a mixture of CH3OH and glacial acetic acid (3:1, 40 mL) was added 10 wt % palladium on activated charcoal (0.20 g, 17 wt %). The suspension was placed in a Parr hydrogenation apparatus under a H2 atmosphere at 50 psi for 1.5 h. The suspension was filtered through diatomaceous earth eluting with CH2Cl2/CH3OH (9:1, 100 mL). Purification by column chromatography (silica gel, 5 to 100% EtOAc in hexanes) afforded methyl 2-amino-5-fluoro-3-hydroxybenzoate (0.80 g, 83%) as a white solid. 1H NMR and MS consistent.
Reaction SMILES: O.[C:2]1([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=[C:4]([OH:5])[CH:3]=1.[CH3:11][S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21](Cl)(=[O:23])=[O:22])(=[O:14])=[O:13]>C([O-])(O)=O.[Na+].ClCCl.O>[CH3:8][C:7]1[CH:9]=[C:2]([O:10][S:21]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[S:12]([CH3:11])(=[O:14])=[O:13])(=[O:23])=[O:22])[CH:3]=[C:4]([OH:5])[CH:6]=1
Reactant: CS(=O)(=O)c1ccccc1S(=O)(=O)Cl
Reactant: Cc1cc(O)cc(O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1cc(O)cc(OS(=O)(=O)c2ccccc2S(C)(=O)=O)c1
Temperature: 25 °C
Yield: 26 %

Procedure:
A mixture of orcinol monohydrate (1.68 g, 12 mmol) and 2-methylsulfonylbenzenesulfonyl chloride (3.0 g, 11.8 mmol) in saturated aqueous NaHCO3 (25 mL) and dichloromethane (25 mL) was stirred vigorously at room temperature for one week. The reaction mixture was diluted with 50 mL of water and extracted into dichloromethane (3×50 mL). The organic phase was washed with brine (2×50 mL) and dried over Na2SO4. After removing the solvent in vacuo, the residue was treated with dichloromethane and ether to initiate crystallization. The mixture was filtered to provide 1.05 g of a white solid. 1H-NMR (300 MHz, CDCl3) δ 2.22 (s, 3H), 3.45 (s, 3H), 5.20 (s, 1H), 6.51 (t, 1H), 6.54 (s, 1H), 6.61 (s, 1H), 7.74 (td, 1H, J=1.4, 7.7 Hz), 7.87 (td, 1H, J=1.3, 7.7 Hz), 8.12 (dd, 1H, J=0.66, 7.8 Hz), and 8.44 (dd, 1H, J 0.52, 7.8 Hz).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH:11]([CH3:12])[CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7]1)=[O:5])C.CO.[OH-].[Li+].Cl>O1CCCC1>[C:16]([O:15][C:13]([N:8]1[CH2:9][CH2:10][C@@H:11]([CH3:12])[C@H:6]([C:4]([OH:5])=[O:3])[CH2:7]1)=[O:14])([CH3:17])([CH3:18])[CH3:19]
Reactant: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCC1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1C(=O)O
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a flask containing (+/−)-4-methyl-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (1.12 g, 4.1 mmol; from example 8 above) was taken up in tetrahydrofuran (12 mL) and methanol (3 mL) and cooled to 0° C. (ice bath). A solution of lithium hydroxide (4.5 mL, 1M) was added and the mixture was warmed to ambient over 3 hours. Extra methanol (2 mL) was added and the material was heated to 60° C. (oil bath) for 5.5 hours. The mixture was cooled to ambient and treated with 1N hydrochloric acid solution (4.7 mL) with vigorous stirring. The solvent was stripped and the remainder was dried under high vacuum for several hours, providing 1.06 g of mainly trans-(+/−)-4-methyl-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester: as a off-white solid. MS (M−H)−=242.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[S:4][C:3]=1[CH3:11].[CH2:12]([CH:14]([C:17]1[C:18]2[N:19]([C:24](I)=[C:25]([CH3:27])[N:26]=2)[N:20]=[C:21]([CH3:23])[CH:22]=1)[CH2:15][CH3:16])[CH3:13]>C1COCC1.[Zn]>[CH2:12]([CH:14]([C:17]1[C:18]2[N:19]([C:24]([C:2]3[C:10]4[C:5](=[CH:6][N:7]=[CH:8][CH:9]=4)[S:4][C:3]=3[CH3:11])=[C:25]([CH3:27])[N:26]=2)[N:20]=[C:21]([CH3:23])[CH:22]=1)[CH2:15][CH3:16])[CH3:13]
Reactant: CCC(CC)c1cc(C)nn2c(I)c(C)nc12
Reactant: Cc1sc2cnccc2c1Br
Agent: [Zn]
Solvent: C1CCOC1
Product: CCC(CC)c1cc(C)nn2c(-c3c(C)sc4cnccc34)c(C)nc12
Temperature: 100 °C
Yield: 15.4 %

Procedure:
190 mg of 3-Bromo-2-methyl-thieno[2,3-c]pyridine (0.83 mmol) is placed into the vial with 1.78 ml of Reiki Zn, suspension in THF (1.25 mmol) and capped and heated at 100° C. for 2 h. The excess Zinc is allowed to settle down and the solution is transferred to the vial containing 172 mg of 8-(1-ethyl-propyl)-3-iodo-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.5 mmol) and 24 mg of PdCl2(pddf) (0.03 mmol) in 3 ml of dry THF. The vial is capped with a Teflon cap and heated at 80° C. overnight. The reaction mixture is quenched with sat. NH4Cl, extracted with CH2Cl2, dried over Na2SO4 and evaporated. The crude product is applied onto a silica-gel chromatography column (Hexane:AcOEt:2 M NH3 in MeOH=20:5:1) to give 28 mg of the title compound. Yield 15%. mass spectrum (m/e): 365 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([CH3:13])[CH:12]=1)[O:5][CH2:6][CH:7](Br)[CH3:8].[I-].[Na+].C(=O)=O.[NH3:19]>CO>[CH3:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([CH3:13])[CH:12]=1)[O:5][CH2:6][CH:7]([NH2:19])[CH3:8]
Reactant: N
Reactant: Cc1cc(C)cc(OCC(C)Br)c1
Agent: O=C=O
Agent: [I-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(C)cc(OCC(C)N)c1
Temperature: 130 °C
Reaction time: 7 h
Yield: 53.8 %

Procedure:
A 20 ml autoclave was charged with 4.20 g (17.3 mmol) of 1-(3,5-dimethylphenoxy)-2-bromopropane, 4 ml of methanol and 0.03 g of sodium iodide, and the autoclave was cooled in a dry ice.acetone bath. The pressure in the autoclave was reduced, and 7 g of liquid ammonia was added. The autoclave was allowed to stand until its temperature reached room temperature, and the mixture was continuously stirred at 130° C. for 7 hours to finish the reaction. After allowed to cool, the reaction mixture was post-treated in the same manner as in Example 26 to give 1.66 g of 1-(3,5-dimethylphenoxy)-2-aminopropane (yield 53.8%).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]([Cl:12])[CH:6]=1)[OH:4].O=[C:14]([CH3:28])[CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:19][CH:18]=1.C1C=CC=CC=1.C([BH3-])#N.[Na+]>CO>[CH3:27][O:26][C:24]([CH2:23][C:20]1[CH:19]=[CH:18][C:17]([O:16][CH2:15][CH:14]([NH:1][CH2:2][CH:3]([C:5]2[CH:6]=[C:7]([Cl:12])[CH:8]=[C:9]([Cl:11])[CH:10]=2)[OH:4])[CH3:28])=[CH:22][CH:21]=1)=[O:25]
Reactant: NCC(O)c1cc(Cl)cc(Cl)c1
Reactant: COC(=O)Cc1ccc(OCC(C)=O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)Cc1ccc(OCC(C)NCC(O)c2cc(Cl)cc(Cl)c2)cc1
Yield: 60 %

Procedure:
Following a procedure similar to that described in Example 3, but using 3.0 g of 2-amino-1-(3,5-dichlorophenyl)ethanol (prepared as described in Preparation 39), 3.87 g of methyl 4-(2-oxopropoxy)phenylacetate (prepared as described in Preparation 3), 80 ml of benzene, 60 ml of absolute methanol and 2.9 g of sodium cyanoborohydride, and then purifying the reaction product by column chromatography through silica gel, using ethyl acetate as the eluent, 3.6 g of the title compound were obtained, having an Rf=0.51 (thin layer chromatography over silica gel, using ethyl acetate as the developing solvent).
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[C:24]1([CH2:30][CH2:31][C:32](O)=[O:33])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:24]1([CH2:30][CH2:31][C:32]([O:23][C@@:9]2([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12][C@@H:13]3[C@H:8]2[CH2:7][CH2:6][N:5]3[C:3]([O:2][CH3:1])=[O:4])=[O:33])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(O)CCc1ccccc1
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Product: COC(=O)N1CC[C@@H]2[C@H]1CCC[C@]2(C#Cc1cccc(C)c1)OC(=O)CCc1ccccc1

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and 3-phenyl-propionic acid to yield (3aR,4S,7aR)-methyl 4-(3-phenylpropanoyloxy)-4-(m-tolylethynyl)octahydro-1H-indole-1-carboxylate. MS [M+H]=296 (ester elimination ion); RT=7.957 min; LC-MS Method II
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([OH:32])([C:28]([F:31])([F:30])[F:29])[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[NH4+:34]>CCO>[NH2:34][C:2]1[N:7]=[N:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([OH:32])([C:28]([F:31])([F:30])[F:29])[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(c1ccc(Cl)nn1)N1CCN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CC1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: Nc1ccc(S(=O)(=O)N2CCN(c3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)nn1
Temperature: 110 °C
Yield: 60.3 %

Procedure:
To a 2 mL microwave vial was added 2-(4-(4-((6-chloropyridazin-3-yl)sulfonyl)piperazin-1-yl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (50 mg, 0.099 mmol), EtOH (1.0 mL) and ammonium hydroxide (2.0 mL, 51 mmol). The solution was heated in an Emrys Optimizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 110° C. for 1 h and then concentrated. The resulting material was purified by silica gel chromatography (0 to 4% MeOH in CH2Cl2) to afford 2-(4-(4-((6-aminopyridazin-3-yl)sulfonyl)piperazin-1-yl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (29 mg) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.40 (s, 1H), 7.67 (d, J=9.4 Hz, 1H), 7.47 (d, J=8.6 Hz, 2H), 7.28 (s, 2H), 7.02 (d, J=9.0 Hz, 2H), 6.89 (d, J=9.2 Hz, 1H), 3.29-3.33 (m, 4H), 3.22-3.28 (m, 4H). m/z (ESI, +ve ion) 485.9 (M+H)+. GK-GKRP IC50 (Binding)=0.285 μM; GK-GKRP EC50 (LC MS/MS-2)=0.302 μM.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([CH2:10][OH:11])[C:7]([F:12])=[CH:6][C:3]=1[C:4]#[N:5].[CH3:13][S:14](Cl)(=[O:16])=[O:15].C(N(CC)CC)C>C(Cl)Cl>[CH3:13][S:14]([O:11][CH2:10][C:8]1[CH:9]=[C:2]([F:1])[C:3]([C:4]#[N:5])=[CH:6][C:7]=1[F:12])(=[O:16])=[O:15]
Reactant: N#Cc1cc(F)c(CO)cc1F
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1cc(F)c(C#N)cc1F
Temperature: 0 °C

Procedure:
To an ice cooled solution of 2,5-difluoro-4-hydroxymethylbenzonitrile (3.10 g, 0.0183 mol; see step (iii) above) and methanesulfonyl chloride (2.21 g, 0.0192 mol) in 60 mL of methylene chloride was added triethyl amine (1.95 g, 0.0192 mol) with stirring. After 1.5 h at 0° C. the mixture was washed with water, dried (Na2SO4) and evaporated. The product could be used without further purification. Yield: 4.5 g (99%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:20]=[C:19]2[C:10]([O:11][C:12]3[C:13]([F:32])=[CH:14][C:15]([N:26]4[CH2:30][CH2:29][CH2:28][C:27]4=[O:31])=[CH:16][C:17]=3[C@@:18]32[CH2:24][O:23][C:22]([NH2:25])=[N:21]3)=[CH:9][CH:8]=1)(=O)=O.[N:35]1[CH:40]=[CH:39][CH:38]=[C:37](B(O)O)[CH:36]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.CN(C=O)C>[NH2:25][C:22]1[O:23][CH2:24][C@:18]2([N:21]=1)[C:19]1[CH:20]=[C:7]([C:37]3[CH:36]=[N:35][CH:40]=[CH:39][CH:38]=3)[CH:8]=[CH:9][C:10]=1[O:11][C:12]1[C:17]2=[CH:16][C:15]([N:26]2[CH2:30][CH2:29][CH2:28][C:27]2=[O:31])=[CH:14][C:13]=1[F:32]
Reactant: OB(O)c1cccnc1
Reactant: NC1=N[C@@]2(CO1)c1cc(OS(=O)(=O)C(F)(F)F)ccc1Oc1c(F)cc(N3CCCC3=O)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NC1=N[C@@]2(CO1)c1cc(-c3cccnc3)ccc1Oc1c(F)cc(N3CCCC3=O)cc12
Temperature: 90 °C

Procedure:
Resealable tube was charged with (S)-2-amino-4′-fluoro-2′-(2-oxopyrolidin-1-yl)-5H-spiro[oxazole-4,9′-xanthene]-7′-yl trifluoromethanesulfonate (130 mg, 0.26 mmol), tetrakis(triphenylphosphine)palladium(0) (30.0 mg, 0.026 mmol), pyridin-3-ylboronic acid (51.0 mg, 0.42 mmol). DMF (1.3 mL) and sodium carbonate (2M, 0.4 mL, 0.8 mmol) were added and the mixture was sealed and heated at 90° C. for 2 h. The mixture was partitioned between water (1 mL) and ethyl acetate (5 mL), organic layer was washed with water, concentrated and purified by FC on 12 g RediSep Gold column using 10-80% DCM/MeOH/NH4OH 90:10:1 in DCM. The fractions containing pure product by TLC were combined and concentrated to afford (S)-1-(2-amino-5′-fluoro-2′-(pyridin-3-yl)-5H-spiro[oxazole-4,9′-xanthene]-7′-yl)pyrolidin-2-one.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:3]=1.[CH:19](B1OB(C=C)OB(C=C)O1)=[CH2:20].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:16][C:15]([F:18])([F:17])[C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:4]2[N:3]=[C:2]([CH:19]=[CH2:20])[N:7]=[CH:6][N:5]=2)=[CH:10][CH:11]=1
Reactant: C=CB1OB(C=C)OB(C=C)O1
Reactant: FC(F)(F)c1ccc(Nc2ncnc(Cl)n2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: C=Cc1ncnc(Nc2ccc(C(F)(F)F)cc2)n1
Temperature: 90 °C
Yield: 16.5 %

Procedure:
To a solution of 4-chloro-N-(4-(trifluoromethyl)phenyl)-1,3,5-triazin-2-amine (0.5 g, 1.821 mmol) in dioxane (8 mL) and water (2 mL) were added trivinylboroxin (0.588 g, 3.64 mmol), cesium carbonate (1.780 g, 5.46 mmol). The reaction mixture was flushed with nitrogen for 10 min and Tetrakis (0.210 g, 0.182 mmol) was added. The reaction mixture was heated at 90° C. for 2 h then filtered through a pad of celite and washed with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated. The crude product was purified by flash chromatography on silica gel using 15% ethyl acetate in hexane to give N-(4-(trifluoromethyl)phenyl)-4-vinyl-1,3,5-triazin-2-amine as a white solid (0.08 g, 12.21% yield). LCMS: R.T.=1.14 min; [M+H]+=267.1.