Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1]N1CCCC1=O.[NH:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]3[N:27]=[C:26]([NH:28][CH2:29][C:30]4[C:35]([F:36])=[CH:34][CH:33]=[C:32]([F:37])[C:31]=4[F:38])[C:25]([C:39]([NH2:41])=[O:40])=[CH:24][N:23]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1.CI.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:1][N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]([NH:21][C:22]3[N:27]=[C:26]([NH:28][CH2:29][C:30]4[C:35]([F:36])=[CH:34][CH:33]=[C:32]([F:37])[C:31]=4[F:38])[C:25]([C:39]([NH2:41])=[O:40])=[CH:24][N:23]=3)=[CH:19][CH:20]=2)[CH2:10][CH2:9]1
Reactant: NC(=O)c1cnc(Nc2ccc(OC3CCNCC3)cc2)nc1NCc1c(F)ccc(F)c1F
Reactant: CN1CCCC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Product: CN1CCC(Oc2ccc(Nc3ncc(C(N)=O)c(NCc4c(F)ccc(F)c4F)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 10 ml portion of 1-methyl-2-pyrrolidone solution containing 800 mg of 2-{[4-(piperidin-4-yloxy)phenyl]amino}-4-[(2,3,6-trifluorobenzyl)amino]-pyrimidine-5-carboxamide was mixed with 0.12 ml of methyl iodide and 300 mg of potassium carbonate, followed by stirring at room temperature for 1 hour and then at 60° C. for 30 minutes. A 0.1 ml portion of methyl iodide was further added thereto, followed by stirring for 30 minutes. The reaction mixture was cooled down to room temperature, mixed with water and then extracted with an ethyl acetate-THF mixed solvent. The organic layer was washed with water and saturated brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by a silica gel column chromatography (chloroform-methanol-aqueous ammonia) and further recrystallized from ethanol to obtain 197 mg of 2-({4-[(1-methylpiperidin-4-yl)oxy]phenyl}amino)-4-[(2,3,6-trifluorobenzyl)amino]pyrimidine-5-carboxamide as colorless crystals.
Reaction SMILES: Cl.Cl.Cl.[NH2:4][C:5]1[C:10]2=[C:11]([C:29]3[S:30][C:31]4[C:37]([O:38][CH3:39])=[CH:36][C:35]([CH3:40])=[CH:34][C:32]=4[CH:33]=3)[C:12]([CH2:21][N:22]3[CH2:27][CH2:26][NH:25][C:24](=[O:28])[CH2:23]3)=[C:13]([CH2:14][N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[N:9]2[N:8]=[CH:7][N:6]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:47](Cl)(=[O:49])[CH3:48]>ClCCl.C1COCC1>[C:47]([N:18]1[CH2:17][CH2:16][N:15]([CH2:14][C:13]2[N:9]3[C:10]([C:5]([NH2:4])=[N:6][CH:7]=[N:8]3)=[C:11]([C:29]3[S:30][C:31]4[C:37]([O:38][CH3:39])=[CH:36][C:35]([CH3:40])=[CH:34][C:32]=4[CH:33]=3)[C:12]=2[CH2:21][N:22]2[CH2:27][CH2:26][NH:25][C:24](=[O:28])[CH2:23]2)[CH2:20][CH2:19]1)(=[O:49])[CH3:48]
Reactant: COc1cc(C)cc2cc(-c3c(CN4CCNC(=O)C4)c(CN4CCNCC4)n4ncnc(N)c34)sc12
Reactant: CC(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1cc(C)cc2cc(-c3c(CN4CCNC(=O)C4)c(CN4CCN(C(C)=O)CC4)n4ncnc(N)c34)sc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of Example 49 (310 mg, 522 μmol) in dichloromethane/THF (2.5:1, 9.64 ml) was treated with sodium carbonate (442 mg, 4.17 mmol) and stirred at rt for 30 min. Acetyl chloride (74 μl, 1.04 mmol) was added, and the resulting mixture was stirred at rt for 2 h. After quenching with methanol, the mixture was evaporated, and the residue was purified by preparative RP-HPLC (Reprosil C18, gradient 10-95% acetonitrile/0.1% aq. formic acid) affording 133 mg (45% of th.) of the title compound.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([N:9]2[CH2:12][CH:11](OS(C)(=O)=O)[CH2:10]2)[O:7][CH:8]=1)(=[O:3])[NH2:2].[C:18]([O-:21])(=[S:20])[CH3:19].[K+]>CN(C)C=O>[C:18]([S:20][CH:11]1[CH2:10][N:9]([C:6]2[O:7][CH:8]=[C:4]([C:1](=[O:3])[NH2:2])[N:5]=2)[CH2:12]1)(=[O:21])[CH3:19]
Reactant: CC([O-])=S
Reactant: CS(=O)(=O)OC1CN(c2nc(C(N)=O)co2)C1
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)SC1CN(c2nc(C(N)=O)co2)C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 63.3 %

Procedure:
To a solution of 1-(4-carbamoyl-1,3-oxazol-2-yl)-3-methanesulfonyloxyazetidine (469 mg, 1.80 mmol) (obtained as described in Reference Example 22(3)) in dimethylformamide (23 ml) was added potassium thioacetate (1.23 g, 10.80 mmol) at room temperature, and the mixture was stirred in an oil bath (80° C.) for 8 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate: methanol (10:1) as the eluant to afford 3-acetylthio-1-(4-carbamoyl-1,3-oxazol-2-yl)azetidine (275 mg, yield 63%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[C:9]([CH3:11])[O:10][C:6]=2[CH:5]=[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:3]=1.[F:17][C:18]1[CH:23]=[C:22](F)[CH:21]=[CH:20][C:19]=1[S:25]([N:28]([CH3:30])[CH3:29])(=[O:27])=[O:26].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.[Cu]I>[CH3:29][N:28]([CH3:30])[S:25]([C:19]1[CH:20]=[CH:21][C:22]([O:1][C:2]2[C:7]3[CH:8]=[C:9]([CH3:11])[O:10][C:6]=3[CH:5]=[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:3]=2)=[CH:23][C:18]=1[F:17])(=[O:27])=[O:26]
Reactant: CCOC(=O)c1cc(O)c2cc(C)oc2c1
Reactant: CN(C)S(=O)(=O)c1ccc(F)cc1F
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(Oc2ccc(S(=O)(=O)N(C)C)c(F)c2)c2cc(C)oc2c1
Temperature: 100 °C
Yield: 88.9 %

Procedure:
A mixture of ethyl 4-hydroxy-2-methyl-1-benzofuran-6-carboxylate (500 mg, 2.27mmol), 2,4-difluoro-N,N-dimethylbenzenesulfonamide (553 mg, 2.75 mmol), Cs2CO3 (1.1 g, 4.12 mmol) and CuI (100 mg, 1 mmol) in DMF (20 mL) was heated to 100° C. for 4 hours. The solvent was removed under reduced pressure. The residue was poured into water (20 mL) and extracted with EtOAc (50 mL×2). The combined organic layers was washed with brine (20 mL×2), dried over Na2SO4 and concentrated. The product was purified via gradient silica gel column chromatography using EtOAc/Hex (10/90 to 30/70) to afford the desired compound (850 mg, 91%) as a white solid. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.41 (t, J=7.16 Hz, 3 H) 2.48 (s, 3 H) 2.78-2.94 (m, 6 H) 4.40 (q, J=7.10 Hz, 2 H) 6.24 (s, 1 H) 6.66-6.94 (m, 2 H) 7.65 (s, 1 H) 7.79 (t, J=8.38 Hz, 1 H) 8.04 (s, 1 H); MS (ESI, pos): 422.
Reaction SMILES: [CH3:1][O:2]C1C=CN=C(C#N)C=1.[C:11]([C:14]1[CH:19]=[C:18](Cl)[CH:17]=[CH:16][N:15]=1)(=[O:13])[CH3:12]>>[C:11]([C:14]1[CH:19]=[C:18]([O:2][CH3:1])[CH:17]=[CH:16][N:15]=1)(=[O:13])[CH3:12]
Reactant: COc1ccnc(C#N)c1
Reactant: CC(=O)c1cc(Cl)ccn1
Product: COc1ccnc(C(C)=O)c1

Procedure:
The title compound was prepared from 4-methoxy-2-piridinecarbonitrile by using the procedure described for the preparation of 2-acetyl4-chloropyridine.
Reaction SMILES: OC(C(F)(F)F)=O.[F:8][C:9]1[CH:10]=[C:11]([C:15]2[N:20]=[CH:19][C:18]([C:21]([NH:23][C@H:24]3[C@@H:28]([OH:29])[CH2:27][NH:26][CH2:25]3)=[O:22])=[CH:17][N:16]=2)[CH:12]=[CH:13][CH:14]=1.Cl[C:31]1[CH:36]=[C:35]([C:37]([C:39]2[S:40][CH:41]=[CH:42][N:43]=2)=[O:38])[CH:34]=[CH:33][N:32]=1>C(O)CCC>[F:8][C:9]1[CH:10]=[C:11]([C:15]2[N:20]=[CH:19][C:18]([C:21]([NH:23][C@H:24]3[C@@H:28]([OH:29])[CH2:27][N:26]([C:31]4[CH:36]=[C:35]([C:37]([C:39]5[S:40][CH:41]=[CH:42][N:43]=5)=[O:38])[CH:34]=[CH:33][N:32]=4)[CH2:25]3)=[O:22])=[CH:17][N:16]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: O=C(c1ccnc(Cl)c1)c1nccs1
Reactant: O=C(N[C@@H]1CNC[C@@H]1O)c1cnc(-c2cccc(F)c2)nc1
Solvent: CCCCO
Solvent: O=C(O)C(F)(F)F
Product: O=C(N[C@@H]1CN(c2cc(C(=O)c3nccs3)ccn2)C[C@@H]1O)c1cnc(-c2cccc(F)c2)nc1
Temperature: 85 °C
Yield: 34 %

Procedure:
To a vial was added cis-2-(3-fluorophenyl)-N-(4-hydroxypyrrolidin-3-yl)pyrimidine-5-carboxamide-TFA salt (50 mg, 0.12 mmol), n-butanol (0.2 mL), TEA (0.016 mL, 0.12 mmol) and (2-chloropyridin-4-yl)(thiazol-2-yl)methanone (40.5 mg, 0.18 mmol. The reaction mixture was heated to 85° C. for 4 hrs and then cooled to rt. The residue mixture was purified by RP-HPLC to give the desired product, cis-2-(3-fluorophenyl)-N-(4-hydroxy-1-(4-(thiazole-2-carbonyl)pyridin-2-yl)pyrrolidin-3-yl)pyrimidine-5-carboxamide (20 mg, 34%). HRMS (M+H) expected=491.1302, observed=491.1357.
Reaction SMILES: [F:1][C:2]1[C:11]2[CH2:10][CH:9]([C:12]3[N:17]=[CH:16][C:15]([OH:18])=[CH:14][N:13]=3)[CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[N:3]=1.[H-].[Na+].[CH2:30](Br)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37].O>CN(C=O)C>[CH2:30]([O:18][C:15]1[CH:14]=[N:13][C:12]([CH:9]2[CH2:10][C:11]3[C:2]([F:1])=[N:3][C:4]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:5][C:6]=3[CH2:7][CH2:8]2)=[N:17][CH:16]=1)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCCCCCBr
Reactant: CCCCCCCCOc1cc2c(c(F)n1)CC(c1ncc(O)cn1)CC2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCOc1cnc(C2CCc3cc(OCCCCCCCC)nc(F)c3C2)nc1
Reaction time: 0.5 h
Yield: 90 %

Procedure:
10 mmol of 1-fluoro-7-(5-hydroxypyrimidin-2-yl)-3-octyloxy-5,6,7,8-tetrahydroisoquinoline are dissolved in 50 ml of DMF, and 11 mmol of sodium hydride are added. After the mixture has been stirred for 30 minutes, 11 mmol of 1-octyl bromide are added dropwise, and the mixture is stirred at 60° C. for a further 140 minutes and poured into water. The mixture is extracted with dichloromethane, the combined organic phases are dried, the solvent is removed in vacuo, and the residue is chromatographed on silica gel, giving 9 mmol of 7-[5-(octyloxy)pyrimidin-2-yl]-1-fluoro-3-octyloxy-5,6,7,8-tetrahydroisoquinoline.
Reaction SMILES: [C:1]1([C@H:7]2[CH2:11][O:10][C:9](=[O:12])[N:8]2[CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][Si]([N-][Si](C)(C)C)(C)C.[Li+].CI>C1COCC1>[C:1]1([C@H:7]2[CH2:11][O:10][C:9](=[O:12])[N:8]2[CH:13]([CH3:18])[C:14]([O:16][CH3:17])=[O:15])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: COC(=O)CN1C(=O)OC[C@@H]1c1ccccc1
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C(C)N1C(=O)OC[C@@H]1c1ccccc1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
A solution of Example 2A (1 g, 4.25 mmol) in 10 mL of anhydrous THF at −78° C. was treated with 4.68 mL (4.68 mmol) of a 1 M solution of lithium bis(trimethylsilyl)amide in THF. The reaction mixture was stirred for 1 h. at about −70° C. before adding MeI (1.59 mL, 25.51 mmol). Upon complete conversion of the azetidinone, the reaction was quenched with saturated aqueous NH4Cl and partitioned between EtOAc and water. The organic layer was washed sequentially with saturated aqueous sodium bisulfite, and saturated aqueous NaCl. The resulting organic layer was dried (MgSO4) and evaporated to afford the title compound (a mixture of diasteromers) as a white solid (1.06 g, 93%); 1H NMR (CDCl3) δ 1.07/1.53 (d/d, J=7.5 Hz, 3H), 3.59/3.74 (s/s, 3H), 3.85/4.48 (q/q, J=7.5 Hz, 1H), 4.10-4.14 (m, 1H), 4.60-4.64/4.65-4.69 (m/m, 1H), 4.88-4.92/4.98-5.02 (m/m, 1H), 7.24-7.40 (m, 5H).
Reaction SMILES: [OH:1][C:2]1([CH2:15][CH:16]=O)[CH2:14][CH2:13][C:5]2([O:10][CH2:9][C:8]([CH3:12])([CH3:11])[CH2:7][O:6]2)[CH2:4][CH2:3]1.[F:18][C:19]([F:31])([F:30])[O:20][C:21]1[CH:26]=[CH:25][C:24]([C@@H:27]([NH2:29])[CH3:28])=[CH:23][CH:22]=1>>[CH3:12][C:8]1([CH3:11])[CH2:9][O:10][C:5]2([CH2:13][CH2:14][C:2]([CH2:15][CH2:16][NH:29][C@H:27]([C:24]3[CH:23]=[CH:22][C:21]([O:20][C:19]([F:18])([F:30])[F:31])=[CH:26][CH:25]=3)[CH3:28])([OH:1])[CH2:3][CH2:4]2)[O:6][CH2:7]1
Reactant: CC1(C)COC2(CCC(O)(CC=O)CC2)OC1
Reactant: C[C@H](N)c1ccc(OC(F)(F)F)cc1
Product: C[C@H](NCCC1(O)CCC2(CC1)OCC(C)(C)CO2)c1ccc(OC(F)(F)F)cc1
Yield: 52 %

Procedure:
The title compound is prepared from (9-hydroxy-3,3-dimethyl-1,5-dioxa-spiro[5.5]undec-9-yl)-acetaldehyde and (S)-1-(4-trifluoromethoxy-phenyl)-ethylamine following a procedure analogous to that described in Step 3 of Intermediate 2. Yield: 52% of theory; LC (method 5): tR=1.13 min; Mass spectrum (ESI+): m/z=432 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:30]=[CH:29][C:6]2[NH:7][C:8]([CH:10]([C:17]3[C:25]([O:26][CH3:27])=[CH:24][C:23]([CH3:28])=[C:22]4[C:18]=3[CH:19]=[CH:20][NH:21]4)[CH:11]([CH3:16])[C:12]([O:14]C)=[O:13])=[N:9][C:5]=2[CH:4]=1)#[N:2].[Li+].[OH-]>CO.O>[C:1]([C:3]1[CH:30]=[CH:29][C:6]2[NH:7][C:8]([CH:10]([C:17]3[C:25]([O:26][CH3:27])=[CH:24][C:23]([CH3:28])=[C:22]4[C:18]=3[CH:19]=[CH:20][NH:21]4)[CH:11]([CH3:16])[C:12]([OH:14])=[O:13])=[N:9][C:5]=2[CH:4]=1)#[N:2]
Reactant: COC(=O)C(C)C(c1nc2cc(C#N)ccc2[nH]1)c1c(OC)cc(C)c2[nH]ccc12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc(C)c2[nH]ccc2c1C(c1nc2cc(C#N)ccc2[nH]1)C(C)C(=O)O
Temperature: 60 °C

Procedure:
To (±)-methyl 3-(5-cyano-1H-benzo[d]imidazol-2-yl)-3-(5-methoxy-7-methyl-1H-indol-4-yl)-2-methylpropanoate (diastereomer A, Example 147-B) (45 mg, 0.11 mmol) was added LiOH (50 mg, 2.0 mmol) in MeOH/Water (3 mL:0.8 mL) and the reaction was heated at 60° C. overnight. The reaction was concentrated, diluted with ethyl acetate (100 mL) and 1 M HCl (20 mL). The organic layer was removed, dried over sodium sulfate and purified via RP-FCC (ACN/water) to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.63-10.91 (m, 1H) 7.97 (br. s., 1H) 7.56 (br. s., 1H) 7.44-7.50 (m, 1H) 7.13-7.18 (m, 1H) 6.74 (s, 1H) 6.26 (br. s., 1H) 5.15 (d, J=9.29 Hz, 1H) 3.82 (s, 3H) 3.61-3.73 (m, 1H) 2.40 (s, 3H) 1.25 (d, J=6.97 Hz, 3H). HRMS calcd. for C22H20N4O3 (M+H)+ 389.1605. found 389.1604.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.C[N:22]1[CH:26]=[C:25](B(O)O)[CH:24]=[N:23]1>>[CH3:20][C:18]1[NH:17][N:16]=[C:15]([NH:14][C:4]2[N:3]=[C:2]([C:25]3[CH:26]=[N:22][NH:23][CH:24]=3)[C:11]3[C:6]([CH:5]=2)=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[CH:19]=1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Reactant: Cn1cc(B(O)O)cn1
Product: COc1ccc2c(-c3cn[nH]c3)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and N-methyl-pyrazole-4-boronic acid to give (5-methyl-1H-pyrazol-3-yl)-[1-(1H-pyrazol-4-yl)-6-methoxy-isoquinolin-3-yl]-amine. LC-MS m/e 335(MH+).
Reaction SMILES: CN(C)S([N:6]1[CH:10]=[C:9]([CH:11]([O:22][CH3:23])[C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[CH:14][CH:13]=2)[N:8]=[C:7]1[Si](C(C)(C)C)(C)C)(=O)=O.Cl>>[NH:6]1[CH:10]=[C:9]([CH:11]([O:22][CH3:23])[C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[CH:14][CH:13]=2)[N:8]=[CH:7]1
Reactant: COC(c1cn(S(=O)(=O)N(C)C)c([Si](C)(C)C(C)(C)C)n1)c1ccnc2ccccc12
Agent: Cl
Product: COC(c1c[nH]cn1)c1ccnc2ccccc12
Yield: 100 %

Procedure:
To 2-(tert-Butyldimethylsilyl)-4-(methoxyquinolin-4-yl-methyl)-imidazole-1-sulfonic acid dimethylamide. (0.32 g, 0.672 mmol), 7 ml of 1.5N HCl was added and the solution refluxed for two hours. The reaction mixture was concentrated, partitioned between water(10 ml) and EtOAc (2×10 ml). The organic layer was dried over sodium sulfate, filtered, concentrated and column purified (CH2Cl2: MeOH: methanol-NH-2 (1.0 M); (4.5:0.25:0.25) to yield 0.160 g (100%) of the product as a syrup.
Reaction SMILES: FC(F)(F)S(O[C@@H:7]([C:12]1[CH:13]=[N:14][C:15]([Cl:18])=[CH:16][CH:17]=1)[C:8]([F:11])([F:10])[F:9])(=O)=O.[F:21][CH2:22][C:23]1([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27][CH2:26][NH:25][CH2:24]1>>[Cl:18][C:15]1[N:14]=[CH:13][C:12]([C@@H:7]([N:25]2[CH2:26][CH2:27][C:23]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])([CH2:22][F:21])[CH2:24]2)[C:8]([F:9])([F:10])[F:11])=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)NC1(CF)CCNC1
Reactant: O=S(=O)(O[C@@H](c1ccc(Cl)nc1)C(F)(F)F)C(F)(F)F
Product: CC(C)(C)OC(=O)NC1(CF)CCN([C@H](c2ccc(Cl)nc2)C(F)(F)F)C1

Procedure:
Prepared as described in Example 9B using (S)-1-(6-chloropyridin-3-yl)-2,2,2-trifluoroethyl trifluoromethanesulfonate (1.10 g, 3.20 mmol) and tert-butyl 3-(fluoromethyl)pyrrolidin-3-ylcarbamate (0.70 g, 3.21 mmol) in place of (S)-tert-butyl pyrrolidin-3-ylcarbamate in Step D (1.03 g, 78%).
Reaction SMILES: [CH3:1][Si:2]([CH3:39])([CH3:38])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:8]1[N:13]2[N:14]=[CH:15][CH:16]=[C:12]2[N:11]=[C:10]([CH:17]2[CH2:22][CH2:21][C:20]([CH2:28][OH:29])([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:19][CH2:18]2)[CH:9]=1.C1C(=O)N([I:47])C(=O)C1>CC#N>[CH3:39][Si:2]([CH3:38])([CH3:1])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([I:47])=[C:12]2[N:11]=[C:10]([CH:17]2[CH2:18][CH2:19][C:20]([CH2:28][OH:29])([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:21][CH2:22]2)[CH:9]=1
Reactant: O=C1CCC(=O)N1I
Reactant: CCOC(=O)C1(CO)CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3nccc3n2)CC1
Solvent: CC#N
Product: CCOC(=O)C1(CO)CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(I)c3n2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.6 %

Procedure:
To a solution of ethyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)-1-(hydroxymethyl)cyclohexanecarboxylate (733 mg, 1.27 mmol) in CH3CN (10 mL) was added NIS (313 mg, 1.39 mmol). The resulting solution was stirred at rt for 30 min before quenching with Na2S2O3 (sat.). CH3CN was removed under reduced pressure. The residue was diluted with EtOAc, washed with H2O and brine, dried over Na2SO4, and concentrated. The crude product was purified by a SiO2 column (0-40% EtOAc/Hexanes, Rf=0.6 in 50% EtOAc) to afford ethyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-iodopyrazolo[1,5-a]pyrimidin-5-yl)-1-(hydroxymethyl)cyclohexanecarboxylate as a colorless oil (811 mg).
Reaction SMILES: C(N(C(C)C)CC)(C)C.Cl[C:11]1[CH:16]=[C:15]([N:17]([CH:25]2[CH2:27][CH2:26]2)[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[N:14]2[N:28]=[CH:29][C:30]([CH:31]=[O:32])=[C:13]2[N:12]=1.[CH2:33]([SH:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(O)C>[CH2:33]([S:40][C:11]1[CH:16]=[C:15]([N:17]([CH:25]2[CH2:27][CH2:26]2)[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[N:14]2[N:28]=[CH:29][C:30]([CH:31]=[O:32])=[C:13]2[N:12]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: SCc1ccccc1
Reactant: CC(C)(C)OC(=O)N(c1cc(Cl)nc2c(C=O)cnn12)C1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(C)(C)OC(=O)N(c1cc(SCc2ccccc2)nc2c(C=O)cnn12)C1CC1
Reaction time: 0.03 h
Yield: 47.1 %

Procedure:
Diisopropylethylamine (256 μL, 1.48 mmol) was added to tert-butyl 5-chloro-3-formylpyrazolo[1,5-a]pyrimidin-7-yl(cyclopropyl)carbamate (250 mg, 0.74 mmol) suspended in ethanol (2.5 mL). Benzyl mercaptan (191 μL, 1.48 mmol) was added and the reaction was homogeneous after ˜2 min. After 10 min, the reaction was diluted with ethanol (3 mL) and the precipitate was filtered and washed with ethanol (10 mL) to yield tert-butyl 5-(benzylthio)-3-formylpyrazolo[1,5-a]pyrimidin-7-yl(cyclopropyl)carbamate (148 mg, 47%). LCMS (ES): >95% pure, m/z 425 [M+1]+.
Reaction SMILES: CN(C)C=O.[Cl-].[Al+3].[Cl-].[Cl-].[C:10]1([CH3:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH:17]12[C:23](=[O:24])[O:22][C:20](=[O:21])[CH:18]1[CH2:19]2>>[C:10]1([CH3:16])[CH:15]=[CH:14][C:13]([C:23]([C@H:17]2[CH2:19][C@H:18]2[C:20]([OH:22])=[O:21])=[O:24])=[CH:12][CH:11]=1
Reactant: Cc1ccccc1
Reactant: O=C1OC(=O)C2CC12
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)[C@H]2C[C@H]2C(=O)O)cc1
Temperature: 70 °C
Yield: 89.7 %

Procedure:
18 ml (0.23 mole) of dimethylformamide are added dropwise in the course of a few minutes, whilst stirring, to 120 g (0.90 mole) of anhydrous aluminum chloride, resulting in a strongly exothermic reaction. 8.2 g (89.0 millimoles) of toluene are then added dropwise at 60°-70° C. Thereafter, 10.0 g (89.2 millimoles) of 1,2-cyclopropanedicarboxylic acid anhydride are added, a little at a time, at the same temperature, and the mixture is stirred for a further hour at 70° C. The melt is then introduced into 1 kg of ice. The solid which has precipitated is filtered off, washed with water and dried under reduced pressure at 50° C. 16.3 g (90% of theory) of cis-2-(p-toluoyl)-cyclopropanecarboxylic acid are obtained as colorless crystals, of melting point 165°-166° C. after recrystallization from ethyl acetate.
Reaction SMILES: OS(O)(=O)=O.O=S(=O)=O.[N+:10]([O-:13])(O)=[O:11].[OH:14][C:15]1[CH:20]=[C:19]([CH2:21][CH3:22])[N:18]=[CH:17][N:16]=1>>[OH:14][C:15]1[C:20]([N+:10]([O-:13])=[O:11])=[C:19]([CH2:21][CH3:22])[N:18]=[CH:17][N:16]=1
Reactant: O=[N+]([O-])O
Reactant: CCc1cc(O)ncn1
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Product: CCc1ncnc(O)c1[N+](=O)[O-]
Reaction time: 8 h

Procedure:
8 ml of 25% oleum are added dropwise with cooling at a maximum of 10° C. to 8 ml of 100% nitric acid. 12.4 g (0.10 mol) of 4-hydroxy-6-ethylpyrimidine are then introduced in portions at a maximum of 35° C. The temperature is kept at 40° C. overnight. For the purpose of reacting further any starting material that remains, a further 13 ml of 25% oleum and 11 ml of 100% nitric acid are added dropwise at a maximum of 40° C. The mixture is left for 12 hours at 40° C. to complete the reaction and is then poured carefully onto ice and extracted completely with ethyl acetate, and the extracts are washed with sodium hydrogen carbonate solution. The extract is concentrated using a rotary evaporator, whereupon 11.8 g (69.7% of the theoretical yield) of pure substance crystallise out; m.p. 181°-183° C.
Reaction SMILES: [Cl:1][C:2]1[C:26]2[O:25][C:9]3[C:10](=[O:24])[N:11]([C@@H:13]([CH2:17][CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)[C:14](O)=[O:15])[CH2:12][C:8]=3[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[NH2:27][C:28]1[S:29][CH:30]=[CH:31][N:32]=1.ON1C2C=CC=CC=2N=N1>C(Cl)Cl.O>[Cl:1][C:2]1[C:26]2[O:25][C:9]3[C:10](=[O:24])[N:11]([C@@H:13]([CH2:17][CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)[C:14]([NH:27][C:28]4[S:29][CH:30]=[CH:31][N:32]=4)=[O:15])[CH2:12][C:8]=3[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Nc1nccs1
Reactant: O=C(O)[C@H](CC1CCCCC1)N1CC2=C(Oc3c(Cl)cccc3C2)C1=O
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: O=C(Nc1nccs1)[C@H](CC1CCCCC1)N1CC2=C(Oc3c(Cl)cccc3C2)C1=O
Yield: 84.1 %

Procedure:
A solution of (S)-2-(5-chloro-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-3-cyclohexyl-propionic acid (100 mg, 0.27 mmol) (Example 20, Step 2c), commercially available 2-aminothiazole (32 mg, 0.32 mmol), N-ethyl-N-dimethyaminopropyl carbodiimide hydrochloride (EDCI. HCl) (40 mg, 0.29 mmol), and N-hydroxybenzotriazole (HOBt) (56 mg, 0.29 mmol) in methylene chloride (5 mL) was stirred for 16 hours at 25° C. The reaction mixture was diluted with water and extracted with ethyl acetate (3×). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue, upon silica gel flash chromatography using hexane-ethyl acetate gradiant elution, afforded (S)-2-(5-chloro-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-3-cyclohexyl-N-thiazol-2-yl-propionamide (104 mg, 85.2%), as a white solid. 1H NMR (DMSO-d6) δ: 12.55 (s, 1H), 7.50 (d, J=2.9 Hz, 1H), 7.40 (d, J=7.8 Hz, 1H), 7.20-7.28 (m, 2H), 7.07-7.17 (m, 1H), 5.07 (dd, J=10.5, 4.2 Hz, 1H), 4.39 (d, J=19.1 Hz, 1H), 4.08 (d, J=18.6 Hz, 1H), 3.84 (br. s., 2H), 1.52-1.90 (m, 7H), 0.76-1.29 (m, 6H).