Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OC(C(F)(F)F)=O.[NH2:8][C@H:9]([CH2:25][F:26])[C@@H:10]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:24])(=[N:20][C:21](=[O:23])[NH2:22])=[O:19])=[CH:14][CH:13]=1)[OH:11].C([O:29][C:30](=O)[CH:31]([Cl:33])[Cl:32])C>CO>[C:21]([N:20]=[S:18]([C:15]1[CH:14]=[CH:13][C:12]([C@@H:10]([OH:11])[C@H:9]([NH:8][C:30](=[O:29])[CH:31]([Cl:33])[Cl:32])[CH2:25][F:26])=[CH:17][CH:16]=1)([CH3:24])=[O:19])(=[O:23])[NH2:22]
Reactant: CS(=O)(=NC(N)=O)c1ccc([C@@H](O)[C@H](N)CF)cc1
Reactant: CCOC(=O)C(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CS(=O)(=NC(N)=O)c1ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 57.8 %

Procedure:
To a solution of (1R,2S)-2-Amino-3-fluoro-1-(4-(N-carbamoyl-S-methylsulfonimidoyl)phenyl)-propan-1-ol TFA salt (250 mg, 0.865 mmol) in Methanol (5 mL) is added TEA (0.175 mL, 1.73 mmol) followed by addition of ethyldichloroacetate (128.72 mL, 1.038 mmol) at room temperature. The resulting reaction mixture is stirred at room temperature for 16 h. Solvent is evaporated in vacuo and obtained crude is purified by combi-flash chromatography using 6% MeOH in DCM as an eluent to give 200 mg of title compound as off white solid. 1H-NMR (400 MHz, DMSO): δ 2.99 (s, 3H), 4.25-4.32 (m, 1.5H), 4.40-4.44 (m, 0.5H), 4.56-4.59 (m, 0.5H), 4.67-4.71 (m, 0.5H), 4.97 (bs, 1H), 6.05 (bs, 1H), 6.18 (m, 1H), 6.46-6.48 (m, 1H), 7.61 (d, J=7.52 Hz, 2H), 7.86 (d, J=8 Hz, 2H), 8.63-8.67 (m, 2H). LC-MS (m/z): M+H=399.8.
Reaction SMILES: [Br: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.[CH3:14][CH:15]1[C:24]2[C:19](=[CH:20][C:21]([C:25]3[C:26]([CH3:30])=[N:27][NH:28][CH:29]=3)=[CH:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][CH:22]=[C:21]([C:25]5[C:26]([CH3:30])=[N:27][NH:28][CH:29]=5)[CH:20]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: Cc1n[nH]cc1-c1ccc2c(c1)CCNC2C
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: Cc1n[nH]cc1-c1ccc2c(c1)CCN(C(=O)c1cc3ncc(Br)cn3n1)C2C

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-6-(3-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [CH:1]([Sn](CCCC)(CCCC)CCCC)=[C:2]([CH3:4])[CH3:3].[NH2:18][C:19]1[CH:24]=[N:23][C:22](Br)=[CH:21][N:20]=1.C(N(CC)C(C)C)(C)C.[Cl-].[Li+]>CN(C)C=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>[NH2:18][C:19]1[CH:24]=[N:23][C:22]([CH:1]=[C:2]([CH3:4])[CH3:3])=[CH:21][N:20]=1
Reactant: CCCC[Sn](C=C(C)C)(CCCC)CCCC
Reactant: Nc1cnc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)=Cc1cnc(N)cn1
Temperature: 130 °C
Reaction time: 4 h
Yield: 25.6 %

Procedure:
A mixture of the crude isobutenyltri-n-butyltin (6.90 g, 58 purity), 2-amino-5-bromopyrazine (1.92 g, 11 mmol), and N,N-diisopropylethylamine (5 mL) in N,N-dimethylformamide (50 mL) was treated with lithium chloride (2.0 g) and tetrakis(triphenylphosphine)palladium(0) (381 mg, 0.33 mmol). The mixture was stirred at 130° C. for 4 h, at which time, thin layer chromatography indicated complete consumption of the starting material. The mixture was concentrated in vacuo. The residue was treated with a saturated aqueous potassium fluoride solution and then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 1.5/1 hexanes/ethyl acetate) afforded 2-amino-5-(2,2-dimethylvinyl)-pyrazine (420 mg, 26%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:28]#[N:29])=[N:4][C:5]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)=[C:12]([C:24]([F:27])([F:26])[F:25])[CH:11]=2)=[CH:6][C:7]=1[NH:8][CH3:9].[N:30]([O-])=O.[Na+]>O.O1CCOCC1.Cl>[CH3:9][N:8]1[C:7]2[CH:6]=[C:5]([C:10]3[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)=[C:12]([C:24]([F:27])([F:26])[F:25])[CH:11]=3)[N:4]=[C:3]([C:28]#[N:29])[C:2]=2[N:1]=[N:30]1
Reactant: O=N[O-]
Reactant: CNc1cc(-c2ccc(OCc3ccncc3)c(C(F)(F)F)c2)nc(C#N)c1N
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cn1nnc2c(C#N)nc(-c3ccc(OCc4ccncc4)c(C(F)(F)F)c3)cc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 68.8 %

Procedure:
To a suspension of 3-amino-4-(methylamino)-6-(4-(pyridin-4-ylmethoxy)-3-(trifluoromethyl)phenyl)picolinonitrile (580 mg) in water (5 ml) and 1,4-dioxane (5 ml), 2N hydrochloric acid (1.089 ml) was added at 0° C. and sodium nitrite (145 mg) in water (1 ml) was added then stirred at 0° C. for 10 min then at 20° C. for 70 h. The reaction mixture was filtered, washed with water, dried in vacuum oven to give 410 mg brown solid. Purified by Biotage SNAP cartridge KP-Sil column (25 g, dichloromethane:methanol=1:0, 20:1 to 10:1) then passed through Strata SCX column (20 g) to give 495 mg brown solid as 1-methyl-6-(4-(pyridin-4-ylmethoxy)-3-(trifluoromethyl)phenyl)-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile (83%).
Reaction SMILES: C[CH2:2][N:3](CC)[CH2:4]C.[CH3:8][N:9]1[C:13]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[O:20][C:21]3([CH2:26][CH2:25][N:24]([C:27]([C:29]4[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=4[C:31]([OH:33])=O)=[O:28])[CH2:23][CH2:22]3)[C:12]=2[CH:11]=[N:10]1.Cl.CNC.CCN=C=NCCCN(C)C>C(Cl)Cl>[CH3:2][N:3]([CH3:4])[C:31](=[O:33])[C:30]1[CH:34]=[CH:35][CH:36]=[CH:37][C:29]=1[C:27]([N:24]1[CH2:25][CH2:26][C:21]2([C:12]3[CH:11]=[N:10][N:9]([CH3:8])[C:13]=3[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[O:20]2)[CH2:22][CH2:23]1)=[O:28]
Reactant: Cn1ncc2c1-c1ccccc1OC21CCN(C(=O)c2ccccc2C(=O)O)CC1
Reactant: CCN(CC)CC
Agent: CCN=C=NCCCN(C)C
Agent: CNC
Agent: Cl
Solvent: ClCCl
Product: CN(C)C(=O)c1ccccc1C(=O)N1CCC2(CC1)Oc1ccccc1-c1c2cnn1C
Reaction time: 16 h
Yield: 35.3 %

Procedure:
Et3N (170 μL, 1.2 mmol) was added to a mixture of 2-(1-methylspiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-carbonyl)benzoic acid (100 mg, 0.25 mmol), N-methylmethanamine hydrochloride (30 mg, 0.37 mmol), EDCI (48 mg, 0.25 mmol), and CH2Cl2 (1.5 mL) at ambient temperature. The mixture was allowed to stir for 16 h before it was diluted with CH2Cl2 and was washed with 1N HCl. The layers were separated and the organic layer was washed with 1N NaOH, and then brine before it was dried over sodium sulfate and was concentrated in vacuo to give N,N-dimethyl-2-(1-methylspiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-carbonyl)benzamide (38 mg) as a white solid. ESI-MS m/z calc. 430.2, found 431.3 (M+1)+; Retention time: 2.24 minutes (3 min run). 1H NMR (400 MHz, CDCl3) δ 7.56 (d, J=7.7 Hz, 1H), 7.45-7.37 (m, 3H), 7.46-7.22 (m, 2H), 7.30-7.21 (m, 1H), 7.13-7.00 (m, 2H), 4.52 (d, J=13.5 Hz, 1H), 4.19 (s, 3H), 3.74-3.51 (m, 2H), 3.31 (t, J=11.9 Hz, 1H), 3.09 (s, 3H), 2.94 (s, 3H), 2.24-2.02 (m, J=13.9 Hz, 2H), 2.02-1.76 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.O.C([O-])(O)=[O:13].[Na+]>OS(O)(=O)=O.C(OC(=O)C)(=O)C>[OH:13][CH2:8][C:5]1[N:4]=[C:3]([C:9]#[N:10])[C:2]([CH3:1])=[CH:7][CH:6]=1
Reactant: O=C([O-])O
Reactant: Cc1ccc(C)c(C#N)n1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: Cc1ccc(CO)nc1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
A solution of 3,6-dimethylpyridine-2-carbonitrile (4.44 g, 30.0 mmol) and conc. H2SO4 (2 drops) in acetic anhydride (30 mL) was stirred at 100° C. for 16 h, cooled to room temperature, poured into water (100 mL) and basified to pH 8 with saturated aqueous NaHCO3. The mixture was extracted with EtOAc (3×25 mL) and the combined organic phase dried (MgSO4) and concentrated in vacuo. The residue was treated with MeOH (100 mL), water (40 mL) and K2CO3 (8.8 g), stirred at room temperature for 1 h, concentrated in vacuo and partitioned between EtOAc and water. The organic phase was dried (MgSO4) and concentrated in vacuo to give the title compound (2.4 g, 51%) as a yellow oil; NMR δH (400 MHz, CDCl3) 2.57 (3H, s), 4.78 (2H, s), 7.42 (1H, d, J 8.5 Hz) and 7.67 (1H, d, J 8.5 Hz); M/Z 149 (M+H)+
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:9][O:10][C:11]([CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[O:12]>>[CH3:9][O:10][C:11]([CH:13]1[CH2:18][CH2:17][N:16]([C:2]2[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:15][CH2:14]1)=[O:12]
Reactant: Clc1cccnc1Cl
Reactant: COC(=O)C1CCNCC1
Product: COC(=O)C1CCN(c2ncccc2Cl)CC1

Procedure:
2,3-Dichloropyridine (1.48 g, 10 mmol, Aldrich) and piperidine-4-carboxylic acid methyl ester (1.43 g, 10 mmol, Aldrich) were reacted under the conditions of Example 3a to give the title compound as a colorless viscous oil. MS (ESI, pos. ion) m/z: 256 (M+1).
Reaction SMILES: [CH2:1]([C:8]1[C:13](Br)=[CH:12][N:11]=[C:10]([CH2:15][CH2:16][CH:17]([OH:19])[CH3:18])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]([C:22]1([OH:30])[CH:27]2[CH2:28][CH2:29][N:24]([CH2:25][CH2:26]2)[CH2:23]1)#[CH:21].C(N(CC)CC)C>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.CN1CCCC1=O>[CH2:1]([C:8]1[C:13]([C:21]#[C:20][C:22]2([OH:30])[CH:27]3[CH2:28][CH2:29][N:24]([CH2:25][CH2:26]3)[CH2:23]2)=[CH:12][N:11]=[C:10]([CH2:15][CH2:16][CH:17]([OH:19])[CH3:18])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(O)CCc1cc(Cc2ccccc2)c(Br)cn1
Reactant: C#CC1(O)CN2CCC1CC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CC(O)CCc1cc(Cc2ccccc2)c(C#CC2(O)CN3CCC2CC3)cn1
Reaction time: 1 h
Yield: 58.1 %

Procedure:
50 mg of 4-benzyl-5-bromo-2-(3-hydroxybutyl)pyridine, 20 mg of 3-ethynyl-3-quinuclidinol, 20 mg of tetrakis(triphenylphosphine)palladium(0), 5 mg of cuprous iodide and 0.5 ml of triethylamine were added to 2 ml of 1-methyl-2-pyrrolidinone, followed by stirring for one hour in an oil bath kept at 110° C. After cooling as it was, it was evaporated. The residue was subjected to NH-silica gel column chromatography and eluted with 5% methanol/ethyl acetate, to give 30 mg of the target compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH2:12])[CH3:11])[N:7]([C@H:13]3[CH2:16][C@@H:15]([O:17][CH3:18])[CH2:14]3)[C:6]=2[CH:19]=1.Cl[C:21]1[N:29]=[CH:28][N:27]=[C:26]2[C:22]=1[N:23]=[CH:24][N:25]2C1CCCCO1.CCN(C(C)C)C(C)C>CC(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH:12][C:21]3[N:29]=[CH:28][N:27]=[C:26]4[C:22]=3[N:23]=[CH:24][NH:25]4)[CH3:11])[N:7]([CH:13]3[CH2:16][CH:15]([O:17][CH3:18])[CH2:14]3)[C:6]=2[CH:19]=1
Reactant: CO[C@H]1C[C@@H](n2c([C@H](C)N)nc3ccc(F)cc32)C1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: COC1CC(n2c([C@H](C)Nc3ncnc4[nH]cnc34)nc3ccc(F)cc32)C1
Temperature: 90 °C
Yield: 51.6 %

Procedure:
To a solution of (S)-1-[6-fluoro-1-(cis-3-methoxycyclobutyl)-1H-benzoimidazol-2-yl]ethylamine (160 mg, 0.61 mmol) in IPA (1.5 mL) was added 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (150 mg, 0.61 mmol) and DIPEA (0.53 mL, 3.1 mmol) and the reaction mixture heated at 90° C. for 16 h. After cooling to RT, the volatiles were removed under reduced pressure and the resulting residue loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined, concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-5% MeOH in DCM) to afford 396 as a white solid (120 mg, 52%). 1H NMR 6 (DMSO-d6): 8.24 (1H, s), 8.14 (1H, s), 7.90 (1H, d, J=7.84 Hz), 7.63 (1H, dd, J=8.82, 5.11 Hz), 7.54 (1H, dd, J=9.80, 2.47 Hz), 7.11-7.02 (1H, m), 5.84 (1H, s), 4.99-4.89 (1H, m), 3.81-3.72 (1H, m), 3.23 (3H, s), 2.96-2.59 (4H, m), 1.64 (3H, d, J=6.70 Hz)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[CH2:5][C@@H:6]([CH2:10][CH2:11][C@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23]C)=[CH:19][CH:18]=1)[C:13]([OH:15])=[O:14])[C:7]([OH:9])=[O:8].Cl.N1C=CC=CC=1>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[CH2:5][C@@H:6]([CH2:10][CH2:11][C@H:12]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([OH:23])=[CH:21][CH:22]=1)[C:13]([OH:15])=[O:14])[C:7]([OH:9])=[O:8]
Reactant: COc1ccc(C[C@@H](CC[C@H](Cc2cccc(Cl)c2)C(=O)O)C(=O)O)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: O=C(O)[C@H](CC[C@H](Cc1cccc(Cl)c1)C(=O)O)Cc1ccc(O)cc1
Temperature: 160 °C
Reaction time: 0.17 h
Yield: 60.7 %

Procedure:
To a round bottom flask was added (2R,5R)-2-(3-Chlorobenzyl)-5-(4-methoxybenzyl)hexanedioic acid (24 mg, 0.061 mmol) and pyridine hydrochloride (71 mg, 0.61 mmol). The reaction was stirred at 160° C. for 10 min. After cooling to rt, the reaction was diluted with water and extracted with EtOAc (2×5 mL). The combined EtOAc extracts were concentrated in vacuum. The resulting residue was purified using RP prep-HPLC (Method B) to give (2R,5R)-2-(3-chlorobenzyl)-5-(4-hydroxybenzyl)hexanedioic acid (14 mg, 0.037 mmol, 61% yield) as white solid. Anal. Calcd. for C20H21ClO5 m/z 376.3. found: 375.2 (M−H)+.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C@H:11]1[C:14](=[O:15])[NH:13][C@@H:12]1[CH2:16][C:17]([C:19]1[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=1)[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[O:18])[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:39]([O:45][CH2:46][O:47][C:48](=[O:52])[C:49](Cl)=[O:50])(=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41]>C(Cl)Cl>[Si:1]([O:8][C@@H:9]([C@H:11]1[C:14](=[O:15])[N:13]([C:49](=[O:50])[C:48]([O:47][CH2:46][O:45][C:39](=[O:44])[C:40]([CH3:41])([CH3:42])[CH3:43])=[O:52])[C@@H:12]1[CH2:16][C:17]([C:19]1[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=1)[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[O:18])[CH3:10])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C(=O)OCOC(=O)C(=O)Cl
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N[C@@H]1CC(=O)c1cccc(C(=O)OC(C)(C)C)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N(C(=O)C(=O)OCOC(=O)C(C)(C)C)[C@@H]1CC(=O)c1cccc(C(=O)OC(C)(C)C)c1
Yield: 99.4 %

Procedure:
tert-Butyl 3-{[(2R,3S)-3-((1R)-1-{[tert-butyl(dimethyl) silyl]oxy}-ethyl)-4-oxo-2-azetidinyl]acetyl}benzoate (2.24 g) and triethylamine (1.11 g) were dissolved in dry methylene chloride (10 ml), and thereto was added dropwise a solution of [(2-chloro-2-oxoacetyl)oxy]methyl pivalate (10 mmol) in dry methylene chloride (10 ml) under ice-cooling. The reaction was quenched by addition of saturated aqueous ammonium chloride solution. The mixture was extracted with ethyl acetate, and separated. The organic layer was washed successively with an aqueous sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give tert-butyl 3-({(2R,3S)-3-((1R)-1-{[tert-butyl(dimethyl) silyl]oxy}ethyl)-1-[{[(2,2-dimethylpropanoyl)oxy]methoxy}(oxo)acetyl]-4-oxo-2-azetidinyl}acetyl)benzoate (3.152 g).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[O:12][C:11](=[O:14])[NH:10][C:9]=2[CH:8]=[C:7]([Cl:15])[CH:6]=1)=O.O1CCCC1.[Li+].[BH4-]>C(OCC)C>[Cl:15][C:7]1[CH:6]=[C:5]([CH2:3][OH:2])[C:13]2[O:12][C:11](=[O:14])[NH:10][C:9]=2[CH:8]=1
Reactant: COC(=O)c1cc(Cl)cc2[nH]c(=O)oc12
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=c1[nH]c2cc(Cl)cc(CO)c2o1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.6 %

Procedure:
5-Chloro-2-oxo-2,3-dihydro-benzooxazole-7-carboxylic acid methyl ester (8 g, 35 mmol) is suspended in diethyl ether (100 mL) and tetrahydrofuran (410 mL) and cooled to zero. The reaction is purged with nitrogen and LiBH4 (6.72 g, 310 mmol) is added portion wise to the reaction. The reaction is warmed to room temperature and stirred for 3 hours. Upon completion the reaction is cooled to 0° C. and quenched by the slow addition of saturated ammonium chloride (250 mL). Water is added to the reaction (500 mL) and the organic layer separated. The water layer is extracted with ethyl acetate (3×100 mL) and the combined organic layers are dried (Na2SO4) filtered and evaporated in vacuo. Product is purified on silica with dichloromethane methanol as the eluent to yield (4.2 g 31 mmol 60%) the title compound (4.2 g 31 mmol 60%). LCMS (ESMS): m/z 200.5 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:5]([OH:12])=[CH:4][CH:3]=1.[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22]O)=[CH:17][CH:16]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH2:22][CH2:21][C:18]2[CH:17]=[CH:16][C:15]([C:14]([F:13])([F:24])[F:25])=[CH:20][CH:19]=2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: OCCc1ccc(C(F)(F)F)cc1
Reactant: COC(=O)c1cc(F)ccc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(F)ccc1OCCc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.2 %

Procedure:
1.79 g (10.5 mmol) of methyl 5-fluorosalicylate, 20 g (10.5 mmol) of 2-(4-trifluoromethylphenyl)ethanol and 2.76 g (10.5 mmol) of triphenylphosphine are introduced into 50 ml of THF and, at 0° C., a solution of 1.83 g (10.5 mmol) of diethyl azodicarboxylate in 10 ml of THF is added dropwise. The mixture is stirred at RT overnight and then the volatile components are removed in vacuo. The resulting crude product is purified by chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 7:1). 2.09 g (58% yield) of the title compound are obtained.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[O:10]1[CH:15]=[CH:14][CH2:13][CH2:12][CH2:11]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1COCC1>[O:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: C1=COCCC1
Reactant: O=Cc1ccc(O)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Product: O=Cc1ccc(OC2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
40.0 g of 4-hydroxybenzaldehyde are dissolved in 400 ml of abs. THF under a protective-gas atmosphere, 55.1 g of dihydropyran and 13.7 g of pyridinium p-toluenesulfonate are added, and the mixture is stirred overnight at room temperature. The solvent is removed in a rotary evaporator, and the residue is subjected to conventional work-up, giving 4-(tetrahydropyran-2-yloxy)benzaldehyde (“BA”) as a colourless oil.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C@:11]([F:15])([CH:13]=[CH2:14])[C:10](=[O:16])[N:9]([CH3:17])[C:8]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[C:32]([O:33][CH3:34])=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[C:25]([F:35])[CH:24]=4)=[N:21][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1>Cl>[CH:1]1([N:6]2[CH2:12][C@:11]([F:15])([CH:13]=[CH2:14])[C:10](=[O:16])[N:9]([CH3:17])[C:8]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[C:32]([O:33][CH3:34])=[CH:31][C:26]([C:27]([OH:29])=[O:28])=[C:25]([F:35])[CH:24]=4)=[N:21][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=C[C@@]1(F)CN(C2CCCC2)c2nc(Nc3cc(F)c(C(=O)OC)cc3OC)ncc2N(C)C1=O
Agent: Cl
Product: C=C[C@@]1(F)CN(C2CCCC2)c2nc(Nc3cc(F)c(C(=O)O)cc3OC)ncc2N(C)C1=O
Temperature: 95 °C
Reaction time: 3.5 h

Procedure:
A mixture of (R)-methyl 4-(9-cyclopentyl-7-fluoro-5-methyl-6-oxo-7-vinyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxybenzoate (400 mg, 0.821 mmol) was suspended in conc. HCl (1.0 mL) and it was stirred at 95° C. for 3-4 hrs. At this time the reaction was cooled to room temperature and filtered to reveal the product as a tan solid (295 mg, 77%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.48-1.82 (m, 4 H) 1.98-2.02 (m, 4 H) 3.29 (s, 3 H) 3.51 (br. s., 2 H) 3.94 (s, 3 H) 4.88 (t, J=8.08 Hz, 1 H) 5.30-5.47 (m, 2 H) 6.01 (ddd, J=17.43, 12.63, 10.86 Hz, 1 H) 7.41-7.57 (m, 1 H) 7.82 (s, 1 H) 8.12 (s, 1 H) 8.31 (d, J=8.08 Hz, 1 H). [M+H] calc'd for C23H25F2N5O4, 474; found 474.
Reaction SMILES: Br[C:2]1[C:31]2=[N:32][C:28]3=[CH:29][N:30]2[C:5]([N:6]2[CH2:38][CH2:37][C:9]([CH3:39])([O:10][CH2:11][CH2:12][CH2:13][CH2:14][C@H:15]([CH3:36])[O:16][C:17]4[CH:18]=[C:19]([F:35])[C:20]([F:34])=[CH:21][C:22]=4[C:23]4[CH:33]=[C:27]3[CH:26]=[CH:25][CH:24]=4)[CH2:8][CH2:7]2)=[C:4]([C@H:40]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[C:41]([O:43][CH3:44])=[O:42])[C:3]=1[CH3:50].[C:51](O[C@@H](C1C(C)=C(C=C)C2=NC3=CN2C=1N1CCC(C)(OCCCC[C@H](C)OC2C=CC(F)=CC=2C2C=C3C=CC=2)CC1)C(OC)=O)(C)(C)[CH3:52]>>[C:46]([O:45][C@@H:40]([C:4]1[C:3]([CH3:50])=[C:2]([CH:51]=[CH2:52])[C:31]2=[N:32][C:28]3=[CH:29][N:30]2[C:5]=1[N:6]1[CH2:7][CH2:8][C:9]([CH3:39])([O:10][CH2:11][CH2:12][CH2:13][CH2:14][C@H:15]([CH3:36])[O:16][C:17]2[CH:18]=[C:19]([F:35])[C:20]([F:34])=[CH:21][C:22]=2[C:23]2[CH:33]=[C:27]3[CH:26]=[CH:25][CH:24]=2)[CH2:37][CH2:38]1)[C:41]([O:43][CH3:44])=[O:42])([CH3:48])([CH3:49])[CH3:47]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)c(Br)c2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1cc(F)c(F)cc1-c1cccc-3c1
Reactant: C=Cc1c(C)c([C@H](OC(C)(C)C)C(=O)OC)c2n3cc(nc13)-c1cccc(c1)-c1cc(F)ccc1O[C@@H](C)CCCCOC1(C)CCN2CC1
Product: C=Cc1c(C)c([C@H](OC(C)(C)C)C(=O)OC)c2n3cc(nc13)-c1cccc(c1)-c1cc(F)c(F)cc1O[C@@H](C)CCCCOC1(C)CCN2CC1
Yield: 84 %

Procedure:
Prepared in 84% yield from methyl(2S)-2-[(22S)-5-bromo-17,18-difluoro-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]-2-(tert-butoxy)acetate following the procedure for methyl(2S)-2-(tert-butoxy)-2-[(22S)-5-ethenyl-17-fluoro-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate. LCMS (ESI, M+1): 702.4.
Reaction SMILES: Cl[C:2]1[CH:14]=[C:6]2[N:7]([CH:11]3[CH2:13][CH2:12]3)[CH2:8][CH2:9][CH2:10][N:5]2[C:4](=[O:15])[N:3]=1.[Cl:16][C:17]1[CH:33]=[CH:32][C:20]([O:21][C:22]2[CH:29]=[CH:28][C:27]([CH2:30][OH:31])=[CH:26][C:23]=2[C:24]#[N:25])=[CH:19][C:18]=1[C:34]([F:37])([F:36])[F:35]>>[Cl:16][C:17]1[CH:33]=[CH:32][C:20]([O:21][C:22]2[CH:29]=[CH:28][C:27]([CH2:30][O:31][C:2]3[CH:14]=[C:6]4[N:7]([CH:11]5[CH2:13][CH2:12]5)[CH2:8][CH2:9][CH2:10][N:5]4[C:4](=[O:15])[N:3]=3)=[CH:26][C:23]=2[C:24]#[N:25])=[CH:19][C:18]=1[C:34]([F:35])([F:36])[F:37]
Reactant: O=c1nc(Cl)cc2n1CCCN2C1CC1
Reactant: N#Cc1cc(CO)ccc1Oc1ccc(Cl)c(C(F)(F)F)c1
Product: N#Cc1cc(COc2cc3n(c(=O)n2)CCCN3C2CC2)ccc1Oc1ccc(Cl)c(C(F)(F)F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for E2 starting from 8-chloro-1-cyclopropyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one and 2-(4-chloro-3-(trifluoromethyl) phenoxy)-5-(hydroxymethyl)benzonitrile.