Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([CH:27]=[C:28]([CH2:30][O:31][C:32]4[CH:41]=[CH:40][C:39]5[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=5)[N:33]=4)[N:29]=3)[C:10]([C:13]3[CH:14]=[CH:15][C:16]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[N:17][CH:18]=3)=[CH:11][N:12]=2)[CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47]>CN(C=O)C.CCOC(C)=O>[C:22]([O:21][C:20]([N:19]([C:16]1[CH:15]=[CH:14][C:13]([C:10]2[N:9]3[CH:27]=[C:28]([CH2:30][O:31][C:32]4[CH:41]=[CH:40][C:39]5[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=5)[N:33]=4)[N:29]=[C:8]3[C:7]([N:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)=[N:12][CH:11]=2)=[CH:18][N:17]=1)[CH2:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])=[O:26])([CH3:23])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cnc(N3CCOCC3)c3nc(COc4ccc5ccccc5n4)cn23)cn1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CN(C(=O)OC(C)(C)C)c1ccc(-c2cnc(N3CCOCC3)c3nc(COc4ccc5ccccc5n4)cn23)cn1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Compound 48a (200.0 mg, 0.450 mmol) was treated with 60% sodium hydride (19.2 mg, 0.48 mmol) in DMF (5 mL) for 15 min. tert-Butyl bromoacetate (25.6 mg, 0.25 mmol) was then added, and the resulting mixture was stirred for 5 h at rt. The reaction was diluted with EtOAc and washed with water. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0-100% EtOAc/heptanes) to give tert-butyl 2-((tert-butoxycarbonyl)(5-(8-morpholino-2-((quinolin-2-yloxy)methyl)imidazo[1,2-a]pyrazin-5-yl)pyridin-2-yl)amino)acetate as an off-white solid, which was subsequently deprotected with TFA following the methods described in the Example 47, Step B to afford the title compound 107 as an off-white solid after trituration with ether. 1H-NMR (400 MHz, CD3OD) δ (ppm): 3.84-3.93 (m, 4H), 4.27 (s, 2H), 4.31-4.39 (m, 4H), 5.66 (s, 2H), 6.97 (d, J=8.8 Hz, 1H), 7.11 (d, J=9.0 Hz, 1H), 7.31 (s, 1H), 7.39-7.45 (m, 1H), 7.66 (ddd, J=8.4, 6.9, 1.3 Hz, 1H), 7.80 (d, J=8.3 Hz, 2H), 7.95-8.01 (m, 2H), 8.12-8.18 (m, 2H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C27H25N7O4: 512.2 [M+H]. found 512.2.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:15]=[N:16][CH:17]=[C:18]([F:20])[CH:19]=2)[C:3]=1[CH3:21].[CH3:22][C:23]1([CH3:38])[C:27]2=[N:28][CH:29]=[C:30]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[CH:31]=[C:26]2[NH:25][CH2:24]1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CC(C)([O-])C.[Na+]>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].C1(C)C=CC=CC=1>[CH3:22][C:23]1([CH3:38])[C:27]2=[N:28][CH:29]=[C:30]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[CH:31]=[C:26]2[N:25]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=3[F:12])[N:5]=[C:4]([C:14]3[CH:15]=[N:16][CH:17]=[C:18]([F:20])[CH:19]=3)[C:3]=2[CH3:21])[CH2:24]1
Reactant: CC1(C)CNc2cc(N3CCOCC3)cnc21
Reactant: Cc1c(-c2cncc(F)c2)nc2cc(F)cc(F)c2c1Cl
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1c(-c2cncc(F)c2)nc2cc(F)cc(F)c2c1N1CC(C)(C)c2ncc(N3CCOCC3)cc21

Procedure:
Prepared according to procedure Y by stirring 4-chloro-5,7-difluoro-2-(5-fluoropyridin-3-yl)-3-methylquinoline (50 mg, 0.162 mmol), 4-(3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)morpholine (37.8 mg, 0.162 mmol), Pd2dba3 (22.3 mg, 0.024 mmol), XPhos (23.2 mg, 0.049 mmol), sodium tert-butoxide (47 mg, 0.486 mmol), and toluene (1.6 mL) at 100° C. for 2 h. Purification by reverse-phase HPLC (0-70% acetonitrile in water) gave 4-(3,3-dimethyl-6-(4-morpholinyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-5,7-difluoro-2-(5-fluoro-3-pyridinyl)-3-methylquinoline. 1H NMR (400 MHz, chloroform-d) δ ppm 8.69-8.76 (1H, m), 8.62 (1H, d, J=2.7 Hz), 7.74-7.80 (1H, m), 7.65-7.70 (1H, m), 7.59-7.62 (1H, m), 7.04 (1H, ddd, J=11.7, 8.9, 2.5 Hz), 5.75 (1H, d, J=2.3 Hz), 3.84-3.88 (1H, m), 3.70-3.81 (5H, m), 2.97-3.06 (4H, m), 2.36 (3H, s), 1.58 (3H, s), 1.47-1.55 (3H, m). Mass Spectrum (ESI) m/e=506.0 (M+1).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C:10]2[CH:11]=[N:12][N:13]([CH3:31])[C:14]=2[C@H:15]2[O:21][CH2:20][C@H:19]([F:22])[C@H:18]([NH:23]C(=O)OC(C)(C)C)[CH2:17][CH2:16]2)=[O:8])[N:6]=1.[F:32][C:33]1[CH:34]=[N:35][CH:36]=[C:37]([F:42])[C:38]=1B(O)O>>[NH2:23][C@H:18]1[C@@H:19]([F:22])[CH2:20][O:21][C@H:15]([C:14]2[N:13]([CH3:31])[N:12]=[CH:11][C:10]=2[NH:9][C:7]([C:5]2[N:6]=[C:2]([C:38]3[C:37]([F:42])=[CH:36][N:35]=[CH:34][C:33]=3[F:32])[S:3][CH:4]=2)=[O:8])[CH2:16][CH2:17]1
Reactant: OB(O)c1c(F)cncc1F
Reactant: Cn1ncc(NC(=O)c2csc(Br)n2)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@@H](F)CO1
Product: Cn1ncc(NC(=O)c2csc(-c3c(F)cncc3F)n2)c1[C@@H]1CC[C@@H](N)[C@@H](F)CO1

Procedure:
Following the procedure for Example 101 starting from tert-butyl ((3R,4R,7S)-7-(4-(2-bromothiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-3-fluorooxepan-4-yl)carbamate (Intermediate 100), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (3,5-difluoropyridin-4-yl)boronic acid gave 247. LCMS (ES+) m/z 453 (M+1).
Reaction SMILES: C[O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[C:6]([O:12][CH3:13])[C:5]=1[F:14].[OH-].[Na+]>C(O)C>[F:14][C:5]1[C:6]([O:12][CH3:13])=[CH:7][C:8]([O:10][CH3:11])=[CH:9][C:4]=1[C:3]([OH:15])=[O:2]
Reactant: COC(=O)c1cc(OC)cc(OC)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(OC)c(F)c(C(=O)O)c1
Yield: 99.7 %

Procedure:
A suspension of 66.7 g (0.27 mol) of 2-fluoro-3,5-dimethoxy-benzoic acid methyl ester and 27 g (0.675 mol) of solid sodium hydroxide in 815 mL of anhydrous ethanol was refluxed for 24 hours. The ethanol was concentrated in vacuo and the solid residue was dissolved in water and extracted two times with ethyl ether. The aqueous layer was acidified with concentrated hydrochloric acid and a white precipitate was filtered, washed with cold water and dried in vacuo to afford 53.9 g (86.5%) of the title compound. MS (APCI) (m+1)/z 201.0.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10](=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[F:14][CH:15]1[CH2:18][NH:17][CH2:16]1.COC(OC)OC.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([N:17]2[CH2:18][CH:15]([F:14])[CH2:16]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: FC1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: COC(OC)OC
Product: CC(C)(C)OC(=O)N1CC(N2CC(F)C2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.7 %

Procedure:
A 10 mL round-bottomed flask was charged with a solution of 3-oxoazetidine-1-carboxylic acid tert-butyl ester (0.14 g, 0.82 mmol), 3-fluoroazetidine hydrochloride (0.1 g, 0.9 mmol) in DCE (3 mL), trimethoxymethane (0.88 mL, 8.5 mmol) and acetic acid (0.046 mL, 0.81 mmol). The reaction mixture was stirred for 3 h at room temperature. Sodium triacetoxyborohydride (0.26 g, 1.22 mmol) was added and the reaction mixture was stirred for 18 h at room temperature. The reaction mixture was partitioned between DCM and water; the organic phase was washed with brine, dried over sodium sulphate and concentrated. The residue was purified by flash chromatography (Si—PPC, EtOAc:cyclohexane, gradient 40:60 to 100:0) to give 3-Fluoro-[1,31biazetidinyl-1′-carboxylic acid tert-butyl ester as a colourless oil (0.109 g, 59%). 1H NMR (CDCl3, 400 MHz) δ 5.15 (dt, J=57.1, 5.3 Hz, 1H); 3.93 (dd, J=9.1, 7.0 Hz, 2H); 3.74-3.59 (m, 4H); 3.45-3.38 (m, 1H); 3.31-3.25 (m, 1H); 3.23-3.17 (m, 1H); 1.43 (s, 9H).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH3:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[C:11]=1[CH:18]([OH:26])[C:19]([Cl:25])([Cl:24])[C:20]([F:23])([F:22])[F:21].N1C=CC=CC=1.Cl>>[CH3:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[C:11]=1[CH:18]([O:26][C:1](=[O:3])[CH3:2])[C:19]([Cl:25])([Cl:24])[C:20]([F:21])([F:22])[F:23]
Reactant: COc1cccc(OC)c1C(O)C(Cl)(Cl)C(F)(F)F
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Product: COc1cccc(OC)c1C(OC(C)=O)C(Cl)(Cl)C(F)(F)F
Temperature: 25 °C
Reaction time: 72 h
Yield: 87 %

Procedure:
31 ml (0.33 mole) of acetic anhydride are added to 97.6 g (0.30 mole) of 1,3-dimethoxy-2-(1-hydroxy-2,2-dichloro-3,3,3-trifluoro-propyl)-benzene in a 500 ml pear-shaped flask at room temperature. 30 ml (0.36 mole) of pyridine are then added to the dark red solution (weakly exothermic). The reaction solution is stirred at room temperature for 3 days. The reaction mixture is then poured onto ice and acidified with 10% hydrochloric acid. It is extracted with ether and the extract is washed with water and brine, dried over magnesium sulfate and evaporated to dryness. The 1,3-dimethoxy-2-(1-acetoxy-2,2-dichloro-3,3,3-trifluoropropyl)-benzene which remains (yield 87%) is employed for stage D without further purification.
Reaction SMILES: C([Li])(C)(C)C.[C:6]([O:10][C:11]([N:13]1[CH:22]2[CH2:23][CH2:24][CH:14]1[C:15]1[CH:16]=[C:17]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH:18]=[CH:19][C:20]=1[CH2:21]2)=[O:12])([CH3:9])([CH3:8])[CH3:7].B(OC)(OC)[O:34]C.OO.Cl>C1COCC1.CO>[C:6]([O:10][C:11]([N:13]1[CH:22]2[CH2:23][CH2:24][CH:14]1[C:15]1[C:16]([OH:34])=[C:17]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH:18]=[CH:19][C:20]=1[CH2:21]2)=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: COB(OC)OC
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1)C1CCC(C2)N1C(=O)OC(C)(C)C
Agent: Cl
Agent: OO
Agent: [Li]C(C)(C)C
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc2c(c1O)C1CCC(C2)N1C(=O)OC(C)(C)C
Temperature: -20 °C
Reaction time: 1 h
Yield: 55.5 %

Procedure:
12-Aza-tricyclo[7.2.1.0*2,7*]dodeca-2(7),3,5-trien-4-ylamine (572 mg, 3.3 mmol), di-tert-butyl dicarbonate (1.6 g, 7.2 mmol), triethylamine (1.0 mL, 7.2 mmol) were stirred at room temperature in tetrahydrofuran (20 mL) for 18 h. The reaction was then concentrated and purified with silica gel chromatography (0-30% EtOAc in hexanes) to obtain 4-tert-Butoxycarbonylamino-12-aza-tricyclo[7.2.1.0*2,7*]dodeca-2(7),3,5-triene-12-carboxylic acid tert-butyl ester as a white solid (1.1 g, 90%). MS (m/e) 375 (M+1). 92b) Tert-butyllithium (1.7M, 2.3 mL, 4.0 mmol) was added dropwise to a solution of 4-tert-butoxycarbonylamino-12-aza-tricyclo[7.2.1.0*2,7*]dodeca-2(7),3,5-triene-12-carboxylic acid tert-butyl ester (450 mg, 1.2 mmol) in THF (5 mL) at −78° C. The solution was then allowed to warm slowly to −20° C. and stir at that temperature for 1 h before cooling again to −78° C. and adding trimethyl borate (0.37 mL, 3.2 mmol) via syringe. The reaction was allowed to warm to room temperature slowly and stir overnight. The reaction was quenched with methanol (1 mL) and hydrogen peroxide (30% solution, 0.37 mL, 3.6 mmol) was added to the reaction and allowed to stir at room temperature for 2 h. The mixture was then adjusted to neutral pH with 1 N HCl, extracted with CH2Cl2 (3×10 mL), dried over MgSO4, filtered and concentrated. The resulting residue was purified with silica gel chromatography (0-50% EtOAc in hexanes) to obtain 4-tert-Butoxycarbonylamino-3-hydroxy-12-aza-tricyclo[7.2.1.0*2,7*]dodeca-2(7),3,5-triene-12-carboxylic acid tert-butyl ester as a brown foam (260 mg, 55%). 1HNMR (400 MHz, CDCl3) δ 7.7 (m, 1H), 7.5 (s, 1H), 7.1 (d, 1H, J=8.1 Hz), 6.9 (m, 1H), 4.5 (d, 1H, J=7.8 Hz), 4.1 (m, 1H), 3.1 (dd, 1H, J=14.4, 4.9 Hz), 2.9 (dd, 1H, J=14.4, 4.9 Hz), 2.7 (dd, 1H, J=18.2, 8.1 Hz), 2.6 (dd, 1H, J=18.2, 10.6 Hz), 2.2-2.1 (m, 1H), 1.5-1.3 (m, 19H); 1H-1H COSY interactions between peak at 7.7 and 7.1 ppm; MS (m/e) 391 (M+1).
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[C:10]([C:28]#[N:29])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:27])=[CH:13][CH:12]=2)=[O:7])CCC.[NH2:30][CH2:31][C:32]([OH:34])=[O:33]>>[C:28]([C:10]1[C:11]2[C:16](=[CH:15][C:14]([O:19][C:20]3[C:21]([CH3:27])=[CH:22][CH:23]=[CH:24][C:25]=3[CH3:26])=[CH:13][CH:12]=2)[C:6]([OH:7])=[C:8]([C:17]([NH:30][CH2:31][C:32]([OH:34])=[O:33])=[O:18])[N:9]=1)#[N:29]
Reactant: CCCCOC(=O)c1nc(C#N)c2ccc(Oc3c(C)cccc3C)cc2c1O
Reactant: NCC(=O)O
Product: Cc1cccc(C)c1Oc1ccc2c(C#N)nc(C(=O)NCC(=O)O)c(O)c2c1

Procedure:
The title compound was synthesized from 1-Cyano-6-(2,6-dimethyl-phenoxy)-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester and glycine in analogy to example 1b; MS-(−)-ion: M−1=390.0.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1.[C:12]1([C:18](=O)[CH2:19][C:20](=O)[CH3:21])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:18]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:19][C:20]([CH3:21])=[N:11]2)=[CH:6][CH:5]=1
Reactant: CC(=O)CC(=O)c1ccccc1
Reactant: COc1ccc(NN)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: COc1ccc(-n2nc(C)cc2-c2ccccc2)cc1
Yield: 53 %

Procedure:
A mixture of 8.7 parts of (4-methoxyphenyl)hydrazine hydrochloride, 8.1 parts of 1-phenyl-1,3-butanedione, 7 parts of potassium carbonate and 160 parts of ethanol is stirred and refluxed for 20 hours. The reaction mixture is cooled and poured onto water. The product is extracted twice with 2,2'-oxybispropane. The combined extracts are washed with water, dried, filtered and evaporated. The residue is crystallized twice from petroleumether. The product is filtered off and dried, yielding 7 parts (53%) of 1-(4-methoxyphenyl)-3-methyl-5phenyl-1H-pyrazole; mp. 110° C.
Reaction SMILES: FC(F)(F)C(O)=O.[I:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[CH2:14][NH:13][CH2:12]2.[O:18](C(OC(C)(C)C)=O)[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=O>N1C=CC=CC=1>[I:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[CH2:14][N:13]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:18])[CH2:12]2
Reactant: Ic1ccc2c(c1)CNC2
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1Cc2ccc(I)cc2C1
Temperature: 70 °C
Reaction time: 1 h
Yield: 78.2 %

Procedure:
A mixture of the product of Step A (0.77 g; 2.15 mmol) and (BOC)2O (0.7 g; 3.2 mmol) in anhydrous pyridine (3 ml) was stirred for 1 h at ˜70° C. After removing solvents under reduced pressure, the residue was diluted to 20 ml with Et2O. The insoluble material was filtered off, and filtrate was washed with diluted HCl (5 ml), saturated NaHCO3 (5 ml), brine and dried over anhydrous MgSO4 and filtered. The filtrate was evaporated under reduced pressure and the residue was purified by FCC (SiO2; CH2Cl2:hexane 1:1) to give title compound (0.58 g; 78%) as creamy oil. 1H-NMR (CDCl3) 1.49 (5, 9H); 4.58-4.63 (m, 4H); 6.9-7.04 (m, 1H); 7.5-7.63 (m, 2H).
Reaction SMILES: [B:1]([OH:4])([OH:3])[OH:2].S([O-])(O)(=O)=O.[CH3:10][N+:11]1[CH:15]=[CH:14][N:13]([CH2:16][CH3:17])[CH:12]=1>O>[B:1]([O-:4])([OH:3])[OH:2].[CH3:10][N+:11]1[CH:15]=[CH:14][N:13]([CH2:16][CH3:17])[CH:12]=1
Reactant: OB(O)O
Agent: CCn1cc[n+](C)c1
Agent: O=S(=O)([O-])O
Solvent: O
Product: [O-]B(O)O

Procedure:
631 g (2.0 mol) of Ba(OH)2 (octahydrate) and 123.6 g (2.0 mol) of boric acid are suspended in 500 ml of water at 60° C. 208 g (1.0 mol) of 1-methyl-3-ethylimidazolium hydrogensulfate are added dropwise to this mixture over a period of 60 minutes. After addition of a further 500 ml of water, the precipitated BaSO4 is filtered off using Celite as filter aid and washed with water. After addition of n-butanol, the water is removed on a rotary evaporator and the residue is dried under reduced pressure to give 247.2 g (1.44 mol) of 1-methyl-3-ethylimidazolium dihydrogenborate (yield: 72%, melting point: 40° C.).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][C:6]#[CH:7].I[C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1/[C:11](=[CH:19]/[C:20]1[NH:21][CH:22]=[CH:23][C:24]=1[O:25][CH3:26])/[C:12](=[O:18])[NH:13]2>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CN(C=O)C.CCN(CC)CC>[OH:1][CH2:2][CH2:3][O:4][CH2:5][C:6]#[C:7][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1/[C:11](=[CH:19]/[C:20]1[NH:21][CH:22]=[CH:23][C:24]=1[O:25][CH3:26])/[C:12](=[O:18])[NH:13]2
Reactant: C#CCOCCO
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(I)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CCOCCO)c21

Procedure:
Using Method C above, 3-(2-hydroxyethoxy)-1-propyne (53 mg, 0.53 mmol) (from Example 21 above) was coupled with (Z)-1,3-dihydro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (150 mg, 0.41 mmol) (Starting Material 2 supra) using (Ph3P)2PdCl2 (20 mg) and CuI (10 mg) as catalyst in DMF (2 mL) and Et3N (2 mL) as solvent at 70° C. for 18 h to yield (Z)-1,3-dihydro-4-[3-(2-hydroxyethoxy)-1-propynyl]-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 68 mg, 49%).
Reaction SMILES: CC(C)=[O:3].C(=O)=O.C(OC[C@@H:17]([CH2:28][N:29]1[CH:34]=[CH:33][C:32]([NH2:35])=[N:31][C:30]1=[O:36])[C@H:18]([O:20][Si](C(C)(C)C)(C)C)[CH3:19])C1C=CC=CC=1.B(Cl)(Cl)Cl.C(Cl)Cl>ClCCl>[NH2:35][C:32]1[CH:33]=[CH:34][N:29]([CH:28]([OH:3])[CH2:17][CH:18]([OH:20])[CH3:19])[C:30](=[O:36])[N:31]=1
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](COCc1ccccc1)Cn1ccc(N)nc1=O
Reactant: CC(C)=O
Agent: ClB(Cl)Cl
Agent: O=C=O
Solvent: ClCCl
Product: CC(O)CC(O)n1ccc(N)nc1=O
Reaction time: 10 h
Yield: 82 %

Procedure:
To a cold (˜−77° C., acetone/dry ice bath) solution of 19 (1.2 g, 2.87 mmol) in 50 ml of anhydrous dichloromethane was added via syringe 19 ml (19 mmol) of 1 M BCl3/CH2Cl2. The reaction was stirred for 10 hrs and quenched with a mixture of methanol (27 ml) and pyridine (13 ml). The reaction was warmed up, concentrated, co-evapoarated with a triethylamine/MeOH mixture to remove pyridine and chromatographed on C18 (5×25 cm) column eluting with a gradient of acetonitrile (0-15%). Concentration of the pure product fractions afforded 0.5 g (82%) of nucleoside 20 as a white solid. 1H NMR (DMSO-d6): δ 7.52 (d, J=7.2 Hz, 1H), 7.01 (br s, 2H), 5.65 (d, J=7.2 Hz), 4.70 (d, J=4.8 Hz, 1H), 4.62 (t, J=5.4 Hz, 1H), 3.84 (m, 1H), 3.63 (m, 2H), 3.34 (m, 1H), 3.25 (m, 1H), 1.68 (m, 1H), 1.08 (d, J=6.3 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[CH:12]1([NH:17][CH2:18][C:19]([F:27])([CH2:25][CH3:26])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:16][CH2:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([N:17]([CH2:18][C:19]([F:27])([CH2:25][CH3:26])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16]2)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: CCOC(=O)C(F)(CC)CNC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C(F)(CC)CN(c1nc(Cl)ncc1[N+](=O)[O-])C1CCCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2,4-dichloro-5-nitropyrimidine (1.4 g, 7.2 mmol) in anhydrous acetone (50 ml) at 0° C., was added dropwise a solution of ethyl 2-((cyclopentylamino)methyl)-2-fluorobutanoate (1.38 g, 6 mmol) in acetone (10 mL) over 10 min. After which, potassium carbonate (2.5 g, 18 mmol) was added and the whole was stirred at rt for 18 h. After evaporation in vacuo, the residue was partitioned between ethyl acetate (200 ml) and water (200 ml). The organic layer was washed with NaHCO3, brine and water, dried over Na2SO4 and concentrated in vacuo to give a red residue which was used directly for next step (2.6 g). [M+H] calc'd for C16H22ClFN4O4, 389. found 389.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[CH:14]=[C:15]4[N:20]([C:21]5[CH:22]=[C:23]([CH:25]=[CH:26][C:27]=5[CH3:28])[NH2:24])[CH:19]=[C:18]([CH3:29])[N:16]4[N:17]=3)[CH:10]=[N:9]2)=[CH:5][CH:4]=1.FC(F)(F)C(O)=O.[CH3:39][N:40]1[CH2:45][CH2:44][N:43]([C:46]2[CH:47]=[C:48]([CH:52]=[C:53]([S:55]([F:60])([F:59])([F:58])([F:57])[F:56])[CH:54]=2)[C:49](O)=[O:50])[CH2:42][CH2:41]1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[CH:14]=[C:15]4[N:20]([C:21]5[CH:22]=[C:23]([NH:24][C:49](=[O:50])[C:48]6[CH:52]=[C:53]([S:55]([F:60])([F:56])([F:57])([F:58])[F:59])[CH:54]=[C:46]([N:43]7[CH2:42][CH2:41][N:40]([CH3:39])[CH2:45][CH2:44]7)[CH:47]=6)[CH:25]=[CH:26][C:27]=5[CH3:28])[CH:19]=[C:18]([CH3:29])[N:16]4[N:17]=3)[CH:10]=[N:9]2)=[CH:30][CH:31]=1
Reactant: CN1CCN(c2cc(C(=O)O)cc(S(F)(F)(F)(F)F)c2)CC1
Reactant: COc1ccc(Cn2cc(-c3cc4n(-c5cc(N)ccc5C)cc(C)n4n3)cn2)cc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Cn2cc(-c3cc4n(-c5cc(NC(=O)c6cc(N7CCN(C)CC7)cc(S(F)(F)(F)(F)F)c6)ccc5C)cc(C)n4n3)cn2)cc1

Procedure:
70 mg (0.17 mmol) of the compound of Example 9A and 78 mg (0.17 mmol) of the compound of Example 17A were reacted and worked up analogously to the procedure of Example 48A. This gave 125 mg (95% of theory) of the title compound.
Reaction SMILES: [C:1]1([CH2:7][C@H:8]([N:12]2[C:16](=[O:17])[C:15]3=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]3[C:13]2=[O:22])[C:9](Cl)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1OC1CC>C1(C)C=CC=CC=1.[Pd]>[C:1]1([CH2:7][C@H:8]([N:12]2[C:16](=[O:17])[C:15]3=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]3[C:13]2=[O:22])[CH:9]=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Cl)[C@H](Cc1ccccc1)N1C(=O)c2ccccc2C1=O
Agent: [Pd]
Agent: CCC1CO1
Solvent: Cc1ccccc1
Product: O=C[C@H](Cc1ccccc1)N1C(=O)c2ccccc2C1=O
Reaction time: 17 h

Procedure:
The solution containing the 3-phenyl-2(S)-phthal-imidoproionyl chloride was diluted with 500 ml of toluene and combined with 72.11 g of 1,2-butylene oxide. 23.5 g of palladium on carbon (5%) and 100 ml of toluene were added to the solution. The suspension was hydrogenated for 17 hours with stirring and then filtered and the residue washed with 200 ml of toluene, wherein 3-phenyl-2(S)-phthalimidopropan-1-al was obtained.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5][C:6](=[O:37])[C:7]2[CH:12]=[C:11]([O:13][CH3:14])[C:10]([NH:15][C:16]3[N:17]=[CH:18][C:19]4[N:25]([CH3:26])[C:24](=[O:27])[C:23]([F:29])([F:28])[CH2:22][N:21]([CH:30]5[CH2:34][CH2:33][CH2:32][CH2:31]5)[C:20]=4[N:35]=3)=[CH:9][C:8]=2F)[CH2:2]1.CCN(C(C)C)C(C)C.[CH3:47][S:48](Cl)(=[O:50])=[O:49]>C(Cl)Cl>[CH:30]1([N:21]2[CH2:22][C:23]([F:28])([F:29])[C:24](=[O:27])[N:25]([CH3:26])[C:19]3[CH:18]=[N:17][C:16]([NH:15][C:10]4[CH:9]=[CH:8][C:7]([C:6]([NH:5][CH:3]5[CH2:4][N:1]([S:48]([CH3:47])(=[O:50])=[O:49])[CH2:2]5)=[O:37])=[CH:12][C:11]=4[O:13][CH3:14])=[N:35][C:20]2=3)[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(C(=O)NC2CNC2)c(F)cc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)NC2CN(S(C)(=O)=O)C2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 8 h
Yield: 8.4 %

Procedure:
To a solution of N-(azetidin-3-yl)-4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxybenzamide (100 mg, 0.19 mmol) in DCM (2.5 mL, 1:2:2) was added DIEA (50 μL, 0.285 mmol), followed by methanesulfonyl chloride (23 μL, 0.21 mmol). After stirring overnight the solvent was removed and the product purified by reverse phase HPLC, free based, and lyophilized to yield a white solid (9.3 mg, 9%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.54-1.79 (m, 6 H) 1.96 (br. s., 2 H) 3.05 (s, 3 H) 3.92 (s, 3 H) 3.94 (d, J=1.77 Hz, 2 H) 4.03-4.15 (m, 4 H) 4.61-4.72 (m, 1 H) 4.76-4.87 (m, 1 H) 7.24 (d, J=6.57 Hz, 1 H) 8.08 (s, 1 H) 8.27 (d, 1 H) 8.31 (s, 1 H) 8.73 (d, J=3.79 Hz, 1 H). [M+H] calc'd for C25H30F3N7O5S, 598; found 598.