Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:34])=[C:4]([C:30]([Cl:33])=[CH:31][CH:32]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([C:15]2[N:20]=[C:19]([NH:21][C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)[C:18]([O:28][CH3:29])=[CH:17][N:16]=2)=[N:7]1.C(N(CC)CC)C.[C:42](OC(=O)C)(=[O:44])[CH3:43].C(=O)([O-])O.[Na+]>CN(C)C=O.C(OCC)(=O)C>[Cl:34][C:3]1[C:4]([CH2:5][N:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]([C:15]3[N:20]=[C:19]([NH:21][C:22]4[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=4)[C:18]([O:28][CH3:29])=[CH:17][N:16]=3)=[N:7]2)=[C:30]([Cl:33])[CH:31]=[CH:32][C:2]=1[NH:1][C:42](=[O:44])[CH3:43]
Reactant: COc1cnc(-c2nn(Cc3c(Cl)ccc(N)c3Cl)c3ccccc23)nc1Nc1ccncc1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cnc(-c2nn(Cc3c(Cl)ccc(NC(C)=O)c3Cl)c3ccccc23)nc1Nc1ccncc1
Reaction time: 3.5 h

Procedure:
50 mg of 2-[1-(3-amino-2,6-dichlorobenzyl)-1H-indazol-3-yl]-5-methoxy-N-(pyridin-4-yl)pyrimidin-4-amine (40-1, 0.102 mmol, 1.0 eq.) were dissolved in 0.6 ml of dry N,N-dimethylformamide. 0.014 ml N,N-diethylethanamine (0.102 mmol, 1.0 eq.) and 0.010 ml acetic anhydride (0.102 mmol, 1.0 eq.) were added at 0° C. and stirred for 3.5 h Then again 0.014 ml N,N-diethylethanamine (0.102 mmol, 1.0 eq.) and 0.010 ml acetic anhydride (0.102 mmol, 1.0 eq.) were added at 0° C. and stirred over night at room temperature. Saturated sodium hydrogen carbonate solution and ethyl acetate were added and the reaction mixture was stirred for 30 min. The organic layer was washed with ethyl acetate twice. The combined organic layers were dried over a silicone filter and concentrated in vacuum. The residue was purified by flash chromatography to yield 17.3 mg (0.03 mmol, 30%) of the analytically pure target compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([C:16]3[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=3[F:23])[C:4]=2[N:5]=[C:6](S(C)=O)[N:7]=1.[NH2:24][CH:25]([CH2:28][OH:29])[CH2:26][OH:27]>ClCCl.CN(C=O)C>[Cl:1][C:2]1[C:3]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([C:16]3[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=3[F:23])[C:4]=2[N:5]=[C:6]([NH:24][CH:25]([CH2:28][OH:29])[CH2:26][OH:27])[N:7]=1
Reactant: NC(CO)CO
Reactant: CS(=O)c1nc(Cl)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=c1ccc2c(Cl)nc(NC(CO)CO)nc2n1-c1c(F)cccc1F
Yield: 41.3 %

Procedure:
A solution of 4-Chloro-2-methylsulfinyl-8-(2,6-difluoro-phenyl)-8H-pyrido[2,3-d]pyrimidin-7-one (0.90 g, 2.53 mmol) in dichloromethane (90 mL) was mixed with a solution of serinol (0.24 g, 2.66 mmol) in DMF (2.0 mL). The resultant mixture was stirred at room temperature for 1 hour before concentrated under vacuum. Flash chromatography (EtOAc/Hexane, 3:1) then provided the title compound (0.40 g, 42%): MS (ES) m/z 383 (M+H)+; 1H-NMR(CDCl3) δ 1.95 (s, br, 2H), 3.90 (m, br, 5H), 6.05 (m, br, 1H), 6.56 (d, J=9.6 Hz, 1H), 7.10 (m, 2H), 7.48 (d, J=8.1 Hz, 2H), 7.94 (d, J=9.6 Hz, 1H).
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[C:7]([O:9][CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:6]=[CH:5][N:4]=1)[NH2:2].O=[C:18]1[CH2:22][S:21][CH2:20][CH:19]1[C:23](OC)=[O:24].C(C1C=CN=C(N2C([O-])=C3CSCC3=N2)C=1)C.[Na+:44]>>[N:13]1[CH:14]=[CH:15][CH:16]=[C:11]([CH2:10][O:9][C:7]2[CH:6]=[CH:5][N:4]=[C:3]([N:1]3[C:23]([O-:24])=[C:19]4[CH2:20][S:21][CH2:22][C:18]4=[N:2]3)[CH:8]=2)[CH:12]=1.[Na+:44]
Reactant: NNc1cc(OCc2cccnc2)ccn1
Reactant: COC(=O)C1CSCC1=O
Agent: CCc1ccnc(-n2nc3c(c2[O-])CSC3)c1
Agent: [Na+]
Product: [O-]c1c2c(nn1-c1cc(OCc3cccnc3)ccn1)CSC2

Procedure:
According to the process described in Example 8, starting with 197 mg of 2-hydrazinyl-4-(pyridin-3-ylmethoxy)pyridine and 146 mg of methyl 4-oxotetrahydrothiophene-3-carboxylate, 225 mg of sodium 2-(4-ethylpyridin-2-yl)-2,6-dihydro-4H-thieno[3,4-c]pyrazol-3-olate are obtained in the form of a white lyophilizate.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[C:19]([CH2:26][S:27][C:28]1[N:29]([CH3:33])[CH:30]=[CH:31][N:32]=1)[C:18]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[C:17]2[C:39]1[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[C:41]([O:47][CH3:48])[CH:40]=1>ClCCl>[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[C:19]([CH2:26][S:27]([C:28]1[N:29]([CH3:33])[CH:30]=[CH:31][N:32]=1)=[O:9])[C:18]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[C:17]2[C:39]1[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[C:41]([O:47][CH3:48])[CH:40]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)c1c(CSc2nccn2C)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Solvent: ClCCl
Product: CCOC(=O)c1c(CS(=O)c2nccn2C)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 69.4 %

Procedure:
m-Chloroperbenzoic acid (85%, 830 mg) was added in small portions under ice-cooling to a solution of ethyl 6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2-[(1-methylimidazol-2-yl)thiomethyl]quinoline-3-carboxylate (3.0 g) in dichloromethane (75 ml). The reaction mixture was stirred at room temperature for 2.5 hours, washed successively with 5% aqueous NaHSO3 solution, saturated aqueous sodium bicarbonate solution and water, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel. The fractions eluted with ethyl acetate/methanol (10/1, v/v) gave ethyl 6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2-[(1-methylimidazol-2-yl)sulfinylmethyl]quinoline-3-carboxylate (1.8 g, 58%) which was then recrystallized from acetone-ethyl ether.
Reaction SMILES: CCN(C(C)C)C(C)C.[N:10]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[C:16]([OH:18])=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.FC(F)(F)C(O)=O.[NH2:47][CH2:48][C:49]([N:51]1[CH2:56][CH2:55][N:54]([C:57](=[O:68])[C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=2[C:64]([F:67])([F:66])[F:65])[CH2:53][CH2:52]1)=[O:50]>CN(C=O)C.O>[O:50]=[C:49]([N:51]1[CH2:52][CH2:53][N:54]([C:57](=[O:68])[C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=2[C:64]([F:67])([F:66])[F:65])[CH2:55][CH2:56]1)[CH2:48][NH:47][C:16]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][N:10]=1)=[O:18]
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Reactant: O=C(O)c1cnccn1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1cnccn1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 33.2 %

Procedure:
DIPEA (78 mg, 0.1 mL, 0.6 mmol) was added to a stirred solution of pyrazine-2-carboxylic acid (25 mg, 0.2 mmol) in DMF (0.5 mL). HOBT (32 mg, 0.24 mmol) and EDCI (46 mg, 0.24 mmol) were then added at room temperature. After 2 minutes, 2-amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone trifluoroacetic acid salt (104 mg, 0.24 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to afford 28 mg (32.9% yield) of pyrazine-2-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-amide. LCMS Purity: 94.8%. 1H NMR (DMSO-d6): δ 9.2 (m, 1H), 8.9 (d, 1H), 8.9-8.8 (bt, 1H), 8.8-8.7 (m, 1H), 7.9-7.8 (m, 1H), 7.8-7.7 (m, 1H), 7.7-7.6 (m, 1H), 7.6-7.5 (m, 1H), 4.3-4.1 (m, 2H), 3.8-3.5 (m, 4H), 3.5-3.4 (m, 2H), 3.2-3.0 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[OH:9].[C:10](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CN(C=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: Cc1ccc(Cl)c(O)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C)ccc1Cl
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 100 %

Procedure:
2-Chloro-5-methylphenol (5.00 g, 35.0 mmol, 1.00 equiv) and potassium carbonate (29.0 g, 2.10 mol, 6 equiv) were combined in DMF and stirred 15 minutes. Dimethyl sulfate (9.95 mL, 1.05 mol, 3.00 equiv) was added and the mixture was heated to 70° C. After 1 hour, the reaction was cooled to room temperature and stirred an additional 18 hours. The mixture was diluted with 200 mL H2O and extracted with Et2O. The organic phase was washed three times with H2O and once with brine, then dried over MgSO4 and concentrated en vacuo. 5.48 g (100%) of the product was obtained as a red liquid. 1H NMR (400 MHz, CDCl3) 7.25 (d, 1H), 6.77 (s, 1H), 6.73 (d, 1H), 3.91 (s, 3H), 2.56 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:11]([O:23][CH3:24])[CH:10]=2)=[O:7])=[C:4]([N+:27]([O-])=O)[CH:3]=1.O.O.[Sn](Cl)Cl>C(O)C>[NH2:27][C:4]1[CH:3]=[C:2]([Cl:1])[CH:26]=[CH:25][C:5]=1[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][N:18]2[CH2:19][CH2:20][CH2:21][CH2:22]2)=[C:11]([O:23][CH3:24])[CH:10]=1)=[O:7]
Reactant: COc1cc(NC(=O)c2ccc(Cl)cc2[N+](=O)[O-])ccc1OCCN1CCCC1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: COc1cc(NC(=O)c2ccc(Cl)cc2N)ccc1OCCN1CCCC1
Yield: 97 %

Procedure:
To a solution of 4-chloro-N-{3-methoxy-4-[2-(1-pyrrolidinyl)ethoxy]phenyl}-2-nitrobenzamide (11.9 mmol, 5.0 g) in ethanol was added tin(II) chloride dihydrate (35.8 mmol, 8.1 g). The resulting mixture was heated to reflux for 4 h and then concentrated by rotary evaporation. The residue was dissolved in ethyl acetate and was washed with potassium sodium tartrate tetrahydrate solution repeatedly. The crude product was first extracted with 2N HCl, then made basic by adding NaOH with ice cooling. The combined basic aqueous solution was extracted with DCM. The organic extraction was washed with brine, dried and concentrated giving the product (4.5 g, 97%). 1H NMR (DMSO-D6): δ 1.67 (4H, m), 2.48 (4H, m), 2.81 (2H, t, J=5.8 Hz), 3.75 (3H, s), 4.10 (2H, t, J=5.8 Hz), 7.02 (1H, d, J=6.2 Hz), 7.10 (1H, d, J=8.6 Hz), 7.16 (1H, s), 7.62 (1H, d, J=8.6 Hz), 7.80 (1H, s), 8.17 (1H, d, 8.6 Hz), 8.35 (1H, s). LCMS m/z=390 (m+H+).
Reaction SMILES: [C:1]12([CH2:11][CH2:12][NH:13][C:14]3[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][C:15]=3[F:21])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[C:22]([CH:25]=[C:26]=[O:27])(=[O:24])[CH3:23]>CCOC(C)=O>[C:1]12([CH2:11][CH2:12][NH:13][C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:26](=[O:27])[CH2:25][C:22](=[O:24])[CH3:23])=[CH:16][C:15]=3[F:21])[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: CC(=O)C=C=O
Reactant: Nc1ccc(NCCC23CC4CC(CC(C4)C2)C3)c(F)c1
Solvent: CCOC(C)=O
Product: CC(=O)CC(=O)Nc1ccc(NCCC23CC4CC(CC(C4)C2)C3)c(F)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 64.5 %

Procedure:
To a solution of N1-(2-(adamantan-1-yl)ethyl)-2-fluorobenzene-1,4-diamine (0.38 g, 1.32 mmol) in EtOAc (20 mL) was added acetyl ketene (0.22 g, 2.62 mmol) and the mixture was stirred at 90° C. overnight. The mixture was then cooled to rt and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=4:1) to give the title compound as a white solid (317 mg, 64%).
Reaction SMILES: C(OC(N(C)[C@@H](C)C(N[C@@H](C(C)(C)C)C(N1[C@H](C(=O)N[C@H]2C3C(=CC=CC=3)CCC2)CC2C(=CC(C(O)=O)=CC=2)C1)=O)=O)=O)(C)(C)C.[C:48]([O:52][C:53]([N:55]1[C@H:59]([C:60]([O:62]C)=[O:61])[CH2:58][CH:57]([C:64]2[CH:73]=[C:72]3[C:67]([CH2:68][C@@H:69]([C:81]([O:83]C)=[O:82])[N:70]([C:74]([O:76][C:77]([CH3:80])([CH3:79])[CH3:78])=[O:75])[CH2:71]3)=[CH:66][CH:65]=2)[CH2:56]1)=[O:54])([CH3:51])([CH3:50])[CH3:49]>>[C:77]([O:76][C:74]([N:70]1[C@H:69]([C:81]([OH:83])=[O:82])[CH2:68][C:67]2[C:72](=[CH:73][C:64]([C@H:57]3[CH2:58][C@@H:59]([C:60]([OH:62])=[O:61])[N:55]([C:53]([O:52][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:54])[CH2:56]3)=[CH:65][CH:66]=2)[CH2:71]1)=[O:75])([CH3:80])([CH3:79])[CH3:78]
Reactant: COC(=O)[C@@H]1Cc2ccc(C3C[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C3)cc2CN1C(=O)OC(C)(C)C
Agent: C[C@@H](C(=O)N[C@H](C(=O)N1Cc2cc(C(=O)O)ccc2C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21)C(C)(C)C)N(C)C(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)N1Cc2cc([C@H]3C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C3)ccc2C[C@H]1C(=O)O
Yield: 95.6 %

Procedure:
Following a procedure analogous to that for the synthesis of Compound K of Example 1, (3S)-2-tert-butyl 3-methyl 7-((5S)-1-(tert-butoxycarbonyl)-5-(methoxycarbonyl)pyrrolidin-3-yl)-3,4-dihydroisoquinoline-2,3(1H)-dicarboxylate (500 mg, 0.96 mmol) was converted to the title compound (450 mg, 95%). MS (ESI+) m/z 491.4 (M+H)+.
Reaction SMILES: COCCOC.[CH2:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:18](I)[S:17][N:16]=2)=[CH:11][CH:10]=1)[CH3:8].[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[CH2:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:18]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[S:17][N:16]=2)=[CH:11][CH:10]=1)[CH3:8]
Reactant: CCOC(=O)c1c(-c2ccc(CC)cc2)nsc1I
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)c1c(-c2ccc(CC)cc2)nsc1-c1ccccc1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
Into a 8-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed ethylene glycol dimethyl ether (2 mL), water (1 mL), ethyl 3-(4-ethylphenyl)-5-iodo-1,2-thiazole-4-carboxylate (50 mg, 0.13 mmol, 1.00 equiv), phenylboronic acid (18.9 mg, 0.16 mmol, 1.20 equiv), Pd(dppf)Cl2 (5.2 mg, 0.01 mmol, 0.06 equiv), sodium carbonate (41 mg, 0.39 mmol, 3.00 equiv). The resulting solution was stirred for 2 h at 90° C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:20). The collected fractions were combined and concentrated under vacuum. This resulted in 56 mg of ethyl 3-(4-ethylphenyl)-5-phenyl-1,2-thiazole-4-carboxylate as yellow oil. Mass spectrum (ESI, m/z): Calcd. for C20H19NO2S, 338.1 (M+H). found 338.1.
Reaction SMILES: C([O:5][C@H:6]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]1[C:19]([F:20])=[CH:18][N:17]=[C:16]([F:21])[N:15]=1)[CH3:7])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:21][C:16]1[N:15]=[C:14]([N:9]2[C@@H:8]([C@@H:6]([OH:5])[CH3:7])[CH2:12][O:11][C:10]2=[O:13])[C:19]([F:20])=[CH:18][N:17]=1
Reactant: C[C@H](OC(C)(C)C)[C@H]1COC(=O)N1c1nc(F)ncc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](O)[C@H]1COC(=O)N1c1nc(F)ncc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.8 %

Procedure:
To a round bottom flask containing (R)-4-((S)-1-(tert-butoxy)ethyl)-3-(2,5-difluoropyrimidin-4-yl)oxazolidin-2-one (590 mg, 1.96 mmol) was added DCM (4 mL) and TFA (4 mL). Resulting reaction mixture stirred for 1 hr at room temperature. The volatiles were then removed. Residue neutralized with a saturated solution of NaHCO3 and aqueous mixture extracted with EtOAc. Organic phases combined, washed with water, brine, dried (Na2SO4), filtered and concentrated to a colorless residue of (R)-3-(2,5-difluoropyrimidin-4-yl)-4-((S)-1-hydroxyethyl)oxazolidin-2-one (470 mg, 1.917 mmol, 98% yield). LCMS m/z 246.0 (M+H)+, Rt 0.41 min.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Br.[P:10]([O:17]CC)([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13]>C1(C)C(C)=CC=CC=1>[CH2:12]([O:11][P:10]([CH2:4][C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[Br:1])(=[O:17])[O:14][CH2:15][CH3:16])[CH3:13]
Reactant: BrCc1ccccc1Br
Reactant: CCOP(OCC)OCC
Solvent: Cc1ccccc1C
Product: CCOP(=O)(Cc1ccccc1Br)OCC
Temperature: 80 °C
Reaction time: 8 h

Procedure:
2-Bromobenzyl bromide (1048 g, 4.2 mol) was melted in a water bath of 60° C. and dissolved in xyleen (734 ml). The solution was heated to 80° C. Next triethyl phosphite (766 ml, 4.46 mol) was added in three equal portions to the reaction mixture in 60 minutes. The mixture was stirred overnight at 110° C. The reaction mixture was co-evaporated twice with 400 ml of xylene. The xylene was removed in vacuo at 60° C. The product was dried in a vacuum oven at 60° C. and was used without further purification.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][C:17]2[CH:26]=[C:25]3[C:20]([C:21]([NH:27][C:28]4[C:36]5[O:35][CH:34]=[CH:33][C:32]=5[CH:31]=[CH:30][C:29]=4[Cl:37])=[N:22][CH:23]=[N:24]3)=[CH:19][C:18]=2[O:38][CH3:39])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:37][C:29]1[CH:30]=[CH:31][C:32]2[CH:33]=[CH:34][O:35][C:36]=2[C:28]=1[NH:27][C:21]1[C:20]2[C:25](=[CH:26][C:17]([O:16][CH2:15][CH2:14][CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[C:18]([O:38][CH3:39])[CH:19]=2)[N:24]=[CH:23][N:22]=1
Reactant: COc1cc2c(Nc3c(Cl)ccc4ccoc34)ncnc2cc1OCCC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc2c(Nc3c(Cl)ccc4ccoc34)ncnc2cc1OCCC1CCNCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.8 %

Procedure:
A mixture of 7-[2-(N-tert-butoxycarbonylpiperidin-4-yl)ethoxy]-4-(6-chlorobenzofuran-7-ylamino)-6-methoxyquinazoline (0.49 g), trifluoroacetic acid (4 ml) and methylene chloride (15 ml) was stirred at ambient temperature for 3 hours. The solvents were evaporated and the residue was diluted with toluene and evaporated again. The residue was partitioned between a mixture of methylene chloride and acetonitrile and a 2N aqueous sodium hydroxide solution. The organic phase was washed with water and with brine, dried over magnesium sulphate and evaporated. The material so obtained was purified by column chromatography using increasingly polar mixtures of methylene chloride and a saturated methanolic ammonia solution. The material so obtained was triturated under diethyl ether to give the title compound (0.296 g); NMR Spectrum: (DMSOd6 and CF3CO2D) 1.4 (m, 2H), 1.75-1.95 (m, 5H), 2.9 (m, 2H), 3.3 (m, 2H), 4.05 (s, 3H), 4.3 (m, 2H), 7.15 (d, 1H), 7.4 (s, 1H), 7.55 (d, 1H), 7.8 (d, 1H), 8.1 (d, 1H), 8.2 (s, 1H), 8.8 (s, 1H), Mass Spectrum: M+H+ 453.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[F:14][C:15]1[CH:24]=[C:23]2[C:18]([CH2:19][CH2:20][NH:21][CH:22]2[CH3:25])=[CH:17][CH:16]=1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:21]3[CH2:20][CH2:19][C:18]4[C:23](=[CH:24][C:15]([F:14])=[CH:16][CH:17]=4)[CH:22]3[CH3:25])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Reactant: CC1NCCc2ccc(F)cc21
Product: CC1c2cc(F)ccc2CCN1C(=O)c1cc2ncc(Cl)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 7-fluoro-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [CH3:1][S:2]([C:5]1[N:10]=[CH:9][C:8]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21](O)=[O:22])=[CH:15]3)=[CH:7][CH:6]=1)(=[O:4])=[O:3].O.O[N:26]1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.N>O.CN(C)C=O>[CH3:1][S:2]([C:5]1[N:10]=[CH:9][C:8]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([NH2:26])=[O:22])=[CH:15]3)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(Oc2ccc3[nH]c(C(=O)O)cc3c2)cn1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(Oc2ccc3[nH]c(C(N)=O)cc3c2)cn1
Temperature: 80 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
A mixture of 5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carboxylic acid (5.2 g), 1-hydroxybenzotriazole monohydrate (3.6 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (4.5 g) and N,N-dimethylformamide (200 mL) was stirred at 80° C. for 1 hr. The reaction mixture was cooled to room temperature and 10% aqueous ammonia (12 mL) was added, and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained crude product was crystallized from diethyl ether to give the title compound (5.18 g, yield 100%) as pale-yellow powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9]([NH:10][C@@H:11]3[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][C@H:12]3[CH2:24][CH3:25])=[C:8]([C:26](=[O:28])[NH2:27])[CH:7]=[N:6][N:5]2[CH:29]=1.FC(F)(F)C(O)=O>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([NH:10][C@@H:11]3[CH2:16][CH2:15][NH:14][CH2:13][C@H:12]3[CH2:24][CH3:25])=[C:8]([C:26]([NH2:27])=[O:28])[CH:7]=[N:6][N:5]2[CH:29]=1
Reactant: CC[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC[C@@H]1CNCC[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of (3R,4R)-tert-butyl 4-((6-bromo-3-carbamoylpyrrolo[1,2-b]pyridazin-4-yl)amino)-3-ethylpiperidine-1-carboxylate (350 mg, 0.750 mmol) in dichloromethane (3.8 ml) cooled to 0° C. was added trifluoroacetic acid (578 μl, 7.50 mmol). The reaction was allowed to warm to room temperature and stirring was continued for 1 hr. After removal of the solvent, the residue was taken into ethyl acetate, washed successively with saturated sodium bicarbonate, water, and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure, yielding 6-bromo-4-(((3R,4R)-3-ethylpiperidin-4-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide (275 mg, 0.75 mmol, 100% yield) as a yellow solid. LCMS (Method K) m/z 368.3 ([M+H]+). Analytical SFC conditions, Column: CC4 from ES Industries; Mobile phase: 10-50% MeOH (with 0.1% DEA) in CO2 in 8 min, 50% MeOH (with 0.1% DEA) in CO2 for 4 more min; Temperature: 40° C., Flow rate: 3 mL/min, BPR: 140 bars, Detection: UV (254 & 220 nm). Retention Time (min): 8.153 (>98.5% ee).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24]O)=[CH:20][CH:19]=2)=[CH2:17])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.CS(Cl)(=O)=O.[CH3:31][N:32]1[C:38]([CH3:40])([CH3:39])[C:36](=[O:37])[NH:35][C:33]1=[O:34].[H-].[Na+]>CCN(CC)CC>[CH3:31][N:32]1[C:38]([CH3:40])([CH3:39])[C:36](=[O:37])[N:35]([CH2:24][C:21]2[CH:22]=[CH:23][C:18]([C:16]([C:3]3[C:2]([CH3:1])=[CH:11][C:10]4[C:9]([CH3:13])([CH3:12])[CH2:8][CH2:7][C:6]([CH3:15])([CH3:14])[C:5]=4[CH:4]=3)=[CH2:17])=[CH:19][CH:20]=2)[C:33]1=[O:34]
Reactant: CN1C(=O)NC(=O)C1(C)C
Reactant: C=C(c1ccc(CO)cc1)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Agent: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCN(CC)CC
Product: C=C(c1ccc(CN2C(=O)N(C)C(C)(C)C2=O)cc1)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Yield: 38.2 %

Procedure:
Adopting the procedure outlined for example 9 using 40.0 mg (0.12 mmol) of {4-[1-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-vinyl]-phenyl}-methanol, 0.05 mL of Methanesulfonyl chloride, 0.10 mL of NEt3, 300 mg of 1,5,5-trimethyl-hydantoin, and 51 mg of NaH, 21.0 mg of the product was obtained.