Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:3]1[C:20](=O)[CH2:19][CH2:18][C@@:17]2([CH3:22])[CH:4]1[C:5](=[O:24])[CH2:6][C@@H:7]1[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]1[CH2:9][CH2:10][C:11]2=[O:23])[CH3:2].[ClH:25].Cl.[NH2:27][CH2:28][CH2:29][O:30][NH2:31]>C1COCC1.O>[ClH:25].[NH2:27][CH2:28][CH2:29][O:30]/[N:31]=[C:20]1/[C@H:3]([CH2:1][CH3:2])[CH:4]2[C@:17]([CH3:22])([CH2:18][CH2:19]/1)[C@@H:16]1[C@H:7]([C@H:8]3[C@@:12]([CH2:14][CH2:15]1)([CH3:13])[C:11](=[O:23])[CH2:10][CH2:9]3)[CH2:6][C:5]2=[O:24]
Reactant: NCCON
Reactant: CC[C@H]1C(=O)CC[C@@]2(C)C1C(=O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CC[C@H]1/C(=N/OCCN)CC[C@@]2(C)C1C(=O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reaction time: 3.5 h

Procedure:
To a stirred solution of 4β-ethylandrostan-3,6,17-trione (Preparation 11, 67 mg) in THF (1.1 ml), a solution of 2-aminoethoxyamine dihydrochloride (31 mg) and Na2HPO4.12H2O (15 mg) in H2O (0.55 ml) was added in portions over 45 minutes. After 3.5 h, the solution was evaporated, water was added and the aqueous phase was extracted with THF. The combined organic extracts were washed with brine, dried over Na2SO4 and evaporated to dryness. The crude product was triturated with Et2O and the precipitate was filtered to give the title compound I-bd (34 mg, 42%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[N:11]/[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:6][CH:5]=1.[P:20]([O-:25])([O:23][CH3:24])[O:21][CH3:22]>CCOC(C)=O>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[P:20]([O:23][CH3:24])([O:21][CH3:22])=[O:25])=[CH:6][CH:5]=1
Reactant: COP([O-])OC
Reactant: COC(=O)c1ccc(/C=N/Cc2ccccc2)cc1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C(NCc2ccccc2)P(=O)(OC)OC)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4-[(E)-Benzylimino-methyl]-benzoic acid methyl ester (0.50 g, 1.97 mmol) was made 0.3 M in dimethyl phosphite (6.5 mL) and to this stirring solution was added catalytic N,N,N,′,N′-tetramethyl-guanidine (0.02 g, 0.20 mmol). After stirring at ambient temperature for 4 hours the reaction mixture was diluted with EtOAc and washed with 1M aqueous NaOH (3×). The organic layer was washed further with brine, then dried (MgSO4) and concentrated in vacuo. MPLC purification (10-70% EtOAc in CH2Cl2) gave the title compound: MS: cal'd 364 (MH+), exp 364 (MH+)
Reaction SMILES: [CH:1]#[CH:2].[Cl:3][SiH:4]([CH:6]([SiH:11]([Cl:13])[Cl:12])[Si:7]([Cl:10])([Cl:9])[Cl:8])[Cl:5]>>[Cl:5][Si:4]1([Cl:3])[CH:2]=[CH:1][Si:11]([Cl:12])([Cl:13])[CH:6]1[Si:7]([Cl:8])([Cl:10])[Cl:9]
Reactant: Cl[SiH](Cl)C([SiH](Cl)Cl)[Si](Cl)(Cl)Cl
Reactant: C#C
Product: Cl[Si](Cl)(Cl)C1[Si](Cl)(Cl)C=C[Si]1(Cl)Cl
Reaction time: 10 h
Yield: 81.4 %

Procedure:
Hydrosilation of acetylene with bis(dichlorosilyl)trichlorosilylmethane in the presence of H2PtCl6. To a 50 ml, three-necked, dried, flask equipped with a magnetic stirrer was added 200 μl of a 0.1 M H2PtCl6 /isopropyl alcohol (IPA) solution. The flask was placed under dry nitrogen atmosphere and the IPA removed under vacuum. Then, 6.29 g of bis(dichlorosilyl)trichlorosilylmethane and 25 ml of dried benzene were added to the flask forming a solution. The solution was maintained at reflux temperature and acetylene gas fed into the solution at a rate of 90 ml per minute for 10 hours. The resulting products were vacuum distilled at 67 Pa to yield 6.36 g of 1,1,3,3-tetrachloro-2-trichlorosilyl-1,3-disilacyclopent-4-ene (TCD-GC are 81.4%) (TCD-GC =gas chromatography using a thermal conductivity detector) and 1,1,3,3-tetrachloro-2-trichlorosilyl-1,3-disilacyclopentane (TCD-GC 4.2%) as a mixture. The structure of 1,1,3,3-tetrachloro-2-trichlorosilyl-1,3-disilacyclopent-4-ene was confirmed by 1H-NMR (CDCl3, ppm): 1.52 (s, 1H, SiCHSi), 7.42 (s, 2H, CH=CH).
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11]N=[CH:9]1)([N:3]1C=CN=C1)=[S:2].N1CC[O:16][CH2:15]C1>C1COCC1>[N:8]1([C:1](=[S:2])[NH2:3])[CH2:12][CH2:11][O:16][CH2:15][CH2:9]1
Reactant: C1COCCN1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: NC(=S)N1CCOCC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 28.1 %

Procedure:
To a stirred solution of 1,1′-thiocarbonyldiimidazole (10.0 g, 56.1 mmol) in THF (150 mL) was added morpholine (4.24 g, 4.2 mL, 48.7 mmol). The reaction was stirred for 72 h at r.t. and then concentrated in vacuo to 30 mL. Ammonia (60 mL, 2.0M in MeOH) was added to the reaction mixture, which was then stirred at r.t. in a sealed flask overnight. The reaction mixture was filtered and the solid washed with Et2O to give the title compound (2.0 g, 28%) as a white solid. δH (DMSO-d6) 7.46 (2H, bs), 3.80-3.60 (4H, m), 3.60-3.50 (4H, m).
Reaction SMILES: [CH2:1]([NH2:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:20]1(=[O:25])[O:24][CH2:23][CH2:22][CH2:21]1>>[OH:25][CH2:20][CH2:21][CH2:22][C:23]([NH:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:24]
Reactant: O=C1CCCO1
Reactant: CCCCCCCC/C=C\CCCCCCCCN
Product: CCCCCCCCC=CCCCCCCCCNC(=O)CCCO
Temperature: 100 °C
Reaction time: 2 h

Procedure:
Oleylamine derived from fat was titrated and found to have an equivalent weight of 266.9 grams (theory=267.5 grams.). In a glass reaction vessel, 266.9 grams of the oleylamine were admixed with 86.1 grams of butyrolactone and the mixture heated to 100° C. on a steam bath until reaction was completed in a period of 2 hours. Greater than 95% conversion of the butyrolactone was achieved. The product upon cooling to room temperature produced a slightly off-white, hard, waxy solid which was found to be readily soluble in alcohols. IR=6.14 mu.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH2:10])[CH:8]=2)[CH:3]=[N:2]1.[Cl:11][C:12]1[N:17]=[C:16]([NH2:18])[N:15]=[C:14](NC2C=CC(Cl)=CC=2)[CH:13]=1>>[Cl:11][C:12]1[N:17]=[C:16]([NH2:18])[N:15]=[C:14]([NH:10][C:7]2[CH:8]=[C:9]3[C:4]([CH:3]=[N:2][NH:1]3)=[CH:5][CH:6]=2)[CH:13]=1
Reactant: Nc1nc(Cl)cc(Nc2ccc(Cl)cc2)n1
Reactant: Nc1ccc2cn[nH]c2c1
Product: Nc1nc(Cl)cc(Nc2ccc3cn[nH]c3c2)n1
Yield: 42 %

Procedure:
Using 1H-indazol-6-yl-amine in place of 4-chloro-phenylamine in the method described in Example 2 for the synthesis of 6-chloro-N*4*-(4-chloro-phenyl)-pyrimidine-2,4-diamine provided 6-chloro-N*4*-(1H-indazol-6-yl)-pyrimidine-2,4-diamine (42% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15](F)[C:16]=3[F:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)=[CH:4][CH:3]=1.Cl.[CH3:26][O:27][C:28]([C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[CH2:35][NH:34][CH2:33]2)=[O:29].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[CH3:26][O:27][C:28]([C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[CH2:35][N:34]([C:15]1[C:16]([F:18])=[C:17]3[C:12]([C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9][N:8]3[C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:13][C:14]=1[F:20])[CH2:33]2)=[O:29]
Reactant: COC(=O)c1ccc2c(c1)CNC2
Reactant: O=C(O)c1cn(-c2ccc(F)cc2)c2c(F)c(F)c(F)cc2c1=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)c1ccc2c(c1)CN(c1c(F)cc3c(=O)c(C(=O)O)cn(-c4ccc(F)cc4)c3c1F)C2
Yield: 9.6 %

Procedure:
170 mg of 1-(4-fluorophenyl)-6,7,8-trifluoro-1,4- dihydro-4-oxoquinoline-3-carboxylic acid, 109 mg of 5-methoxycarbonylisoindoline hydrochloride, 228 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 24 mg of the target compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].O[CH:29]1CCCNC1.CCN(C(C)C)C(C)C>CC(O)C>[Br:1][C:2]1[C:3]([N:22]2[CH2:26][CH2:29][CH2:25][CH:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:18])[F:19])=[CH:12][CH:11]=1)=[O:8]
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Reactant: OC1CCCNC1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CCCC(O)C2)c(Br)c1
Temperature: 25 °C

Procedure:
5-Bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Example 35, 1 g, 2.53 mmol), 3-hydroxypiperidine (307 mg, 3.03 mmol) and DIPEA (883 μL, 5.06 mmol) in iPrOH (2528 μL) were added to a MW vial and subjected to MW irradiation at 140° C. for 60 min. The vial was cooled to RT and the RM was evaporated to dryness under reduced pressure, treated with 0.5 M HCl (25 mL) and extracted with EtOAc. The combined extracts were washed with HCl 0.5 M, brine, dried over MgSO4 and evaporated to dryness under reduced pressure. The crude product was purified by flash chromatography (Silica gel column, 24 g, cyclohexane/EtOAc-EtOH+0.1% NH4OH (9:1)), from 15% to 60% EtOAc-EtOH+0.1% NH4OH (9:1)) to afford the title compound as a white foam. UPLC-MS (condition 1) tR=2.89 min, m/z=460.0-462.0 [M+H]+, m/z=458.0-460.0 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.27-1.45 (m, 1H) 1.46-1.66 (m, 1H) 1.73-1.87 (m, 1H) 1.89-2.01 (m, 1H) 2.74 (dd, J=12.23, 9.29 Hz, 1H) 2.92 (t, J=10.64 Hz, 1H) 3.56-3.70 (m, 1H) 3.70-3.81 (m, 1H) 3.91 (dd, J=12.10, 3.30 Hz, 1H) 4.87 (d, J=4.40 Hz, 1H) 7.36 (d, J=8.56 Hz, 2H) 7.85 (d, J=9.05 Hz, 2H) 8.42 (d, J=1.96 Hz, 1H) 8.76 (d, J=1.96 Hz, 1H) 10.37 (s, 1H).
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.[OH:39][C:40]1[CH:45]=[CH:44][C:43](B(O)O)=[CH:42][CH:41]=1.C(=O)([O-])[O-].[Na+].[Na+]>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>[OH:39][C:40]1[CH:45]=[CH:44][C:43]([C:2]2[C:10]3[C:9]([NH:11][C@H:12]([C:14]4[N:19]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[C:18](=[O:26])[C:17]5=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]5[N:15]=4)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=3[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=2)=[CH:42][CH:41]=1
Reactant: OB(O)c1ccc(O)cc1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3ccc(O)cc3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Yield: 60.8 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (80 mg, 0.13 mmol) was treated with (4-hydroxyphenyl)boronic acid (45 mg, 0.32 mmol), sodium carbonate (34 mg, 0.32 mmols) and bis(triphenylphosphine)palladium(II) dichloride (9 mg, 0.01 mmol) according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 60%, hexane-ethyl acetate) to give 48 mg (58% yield) of the title compound. Purity 96%.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:5](=[C:7]([CH2:11][OH:12])[CH:8]=[CH:9][CH:10]=2)[CH:6]=1.CS(C)=O.C(Cl)(=O)C(Cl)=O>C(N(CC)CC)C>[CH3:1][C:2]1[O:3][C:4]2[C:5](=[C:7]([CH:11]=[O:12])[CH:8]=[CH:9][CH:10]=2)[CH:6]=1
Reactant: Cc1cc2c(CO)cccc2o1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1cc2c(C=O)cccc2o1
Yield: 93.4 %

Procedure:
2-Methyl-benzofuran-4-methanol (3.34 g, 21 mmol) was oxidized using DMSO, oxalyl chloride, and triethyl amine similar to the above procedures to give the product as a clear oil (3.14 g, 93%).
Reaction SMILES: [N:1]1([CH:6]([C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH3:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:19][CH:20]([CH3:24])[C:21](O)=[O:22]>>[N:1]1([CH:6]([C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:21](=[O:22])[CH:20]([Br:19])[CH3:24])[CH3:7])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(c1cccc(OCCCN)c1)N1CCCC1
Reactant: CC(Br)C(=O)O
Product: CC(Br)C(=O)NCCCOc1cccc(C(C)N2CCCC2)c1

Procedure:
3-[3-[1-(1-Pyrrolidinyl)ethyl]phenoxy]propylamine and bromopropionic acid were reacted in the same way as in Example 6 to afford N-[3-[3-[1-(1-pyrrolidinyl)ethyl]phenoxy]propyl]bromopropionamide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18](OC4C(F)=C(F)C(F)=C(F)C=4F)(=[O:20])=[O:19])=[CH:15][CH:16]=3)[N:11]=[CH:10][N:9]=2)[C:5]([O:33][CH3:34])=[CH:4][C:3]=1[C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=1.[N:42]1[CH:47]=[CH:46][C:45]([NH2:48])=[N:44][CH:43]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([NH:48][C:45]4[CH:46]=[CH:47][N:42]=[CH:43][N:44]=4)(=[O:19])=[O:20])=[CH:15][CH:16]=3)[N:11]=[CH:10][N:9]=2)[C:5]([O:33][CH3:34])=[CH:4][C:3]=1[C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=1
Reactant: COc1cc(-c2cccc(F)c2)c(Cl)cc1-c1ncnc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Reactant: Nc1ccncn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(-c2cccc(F)c2)c(Cl)cc1-c1ncnc2cc(S(=O)(=O)Nc3ccncn3)ccc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85.7 %

Procedure:
A flask was charged with perfluorophenyl 4-(2-chloro-3′-fluoro-5-methoxy-[1,1′-biphenyl]-4-yl)quinazoline-7-sulfonate (Intermediate ZZZZZ; 0.060 g, 0.098 mmol), pyrimidin-4-amine (9.81 mg, 0.103 mmol), and THF (0.982 ml) and cooled to 0° C. LHMDS (1.0M in THF) (0.206 ml, 0.206 mmol) was added drop wise and the reaction was stirred for 30 minutes. The reaction was quenched with saturated ammonium chloride solution, diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (RediSep Gold 80 g, gradient elution 0-10% MeOH:DCM) to afford 4-(2-chloro-3′-fluoro-5-methoxy-[1,1′-biphenyl]-4-yl)-N-(pyrimidin-4-yl)quinazoline-7-sulfonamide (0.044 g, 0.084 mmol, 86% yield) as an -off-white solid. 1H NMR (400 MHz, DMSO-d6) δ=9.49 (s, 1H), 8.57 (s, 1H), 8.51 (d, J=1.6 Hz, 1H), 8.22 (d, J=6.9 Hz, 1H), 8.08 (dd, J=1.8, 8.8 Hz, 1H), 7.91 (d, J=8.9 Hz, 1H), 7.67 (s, 1H), 7.59 (dt, J=6.3, 8.1 Hz, 1H), 7.48-7.41 (m, 2H), 7.37-7.29 (m, 2H), 7.00 (d, J=5.0 Hz, 1H), 3.74 (s, 3H). m/z (ESI) 522.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.OS(O)(=O)=O.OO.[CH3:15][NH:16][CH:17]=[O:18]>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:17]([NH:16][CH3:15])=[O:18])[CH:3]=1
Reactant: Clc1ccncc1
Reactant: CNC=O
Agent: O=S(=O)(O)O
Agent: OO
Product: CNC(=O)c1cc(Cl)ccn1
Temperature: 60 °C
Reaction time: 1 h
Yield: 5.3 %

Procedure:
Caution: this is a highly hazardous, potentially explosive reaction. To a stirring solution of 4-chloropyridine (10.0 g) in N-methylformamide (250 mL) at room temp. was added conc. H2SO4 (3.55 mL) to generate an exotherm. To this mixture was added H2O2 (30% wt in H2O, 17 mL) followed by FeSO4.7H2O (0.56 g) to generate another exotherm. The resulting mixture was stirred in the dark at room temp. for 1 h, then warmed slowly over 4 h to 45° C. When bubbling had subsided, the reaction was heated at 60° C. for 16 h. The resulting opaque brown solution was diluted with H2O (700 mL) followed by a 10% NaOH solution (250 mL). The resulting mixture was extracted with EtOAc (3×500 mL). The organic phases were washed separately with a saturated NaCl solution (3×150 mL), then they were combined, dried (MgSO4) and filtered through a pad of silica gel with the aid of EtOAc. The resulting brown oil was purified by column chromatography (gradient from 50% EtOAc/50% hexane to 80% EtOAc/20% hexane). The resulting yellow oil crystallized at 0° C. over 72 h to give 4-chloro-N-methyl-2-pyridinecarboxamide (0.61 g, 5.3%): TLC (50% EtOAc/50% hexane) Rf0.50; 1H NMR (CDCl3) δ 3.04 (d, J=5.1 Hz, 3H), 7.43 (dd, J=5.4, 2.4 Hz, 1H), 7.96 (brs, 1H), 8.21 (s, 1H), 8.44 (d, J=5.1 Hz, 1 H); CI-MS m/z 171 ((M+H)+).
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1.C(OCC)(=O)C.O.[CH3:22][N:23](C)C=O>[C-]#N.[Zn+2].[C-]#N.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>[O:4]([C:5]1[N:6]=[C:7]([C:22]#[N:23])[CH:8]=[CH:9][CH:10]=1)[C:3]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:2]=1
Reactant: Brc1ccccc1Oc1ccccn1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1cccc(Oc2ccccc2)n1
Temperature: 100 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
Next, to a solution of the resulting 2-bromo-phenoxy-pyridine (1.0 g, 4.0 mmol) in N,N-dimethylformamide (30 mL) were added zinc cyanide (940 mg, 8.0 mmol) and tetrakis(triphenylphosphine)palladium(0) (924 mg, 0.8 mmol) under nitrogen atmosphere, and the mixture was stirred at 100° C. for 1 hour. The reaction mixture was allowed to room temperature, ethyl acetate and water were added for partitioning, the organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1), and 6-phenoxy-pyridine-2-carbonitrile (524 mg, 67%) was obtained as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[C:25](O)([CH3:28])([CH3:27])[CH3:26].N>O1CCCC1>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(O)cc1
Reactant: CC(C)(C)O
Agent: N
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Cc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
76.5 g (0.5 mols) of p-hydroxyphenylacetic acid was dissolved in 500 ml of tetrahydrofuran (THF). The resulting reaction solution was then cooled to a temperature of from −20° C. to −15° C. To the reaction solution was then added dropwise 231 g (1.1 mols) of trifluoroacetic anhydride. After the termination of dropwise addition, the reaction mixture was stirred at room temperature for 12 hours. The reaction solution was then again cooled to a temperature of from −20° C. to −15° C. To the reaction solution was then added dropwise 37 g (0.5 mols) of t-butanol. The reaction mixture was then stirred at room temperature for 3 hours. To the reaction solution was then added dropwise 100 ml of aqueous ammonia. The reaction mixture was then extracted with water to obtain t-butyl p-hydroxyphenylacetate.
Reaction SMILES: [C:1]([C:3]1[CH:24]=[CH:23][C:6]([O:7][CH2:8][C@H:9]([OH:22])[CH2:10][NH:11][C:12](=[O:21])[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:5][CH:4]=1)#[N:2].[CH3:25][S:26](Cl)(=[O:28])=[O:27]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[CH3:25][S:26]([O:22][C@@H:9]([CH2:8][O:7][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:24][CH:23]=1)[CH2:10][NH:11][C:12]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:21])(=[O:28])=[O:27]
Reactant: CS(=O)(=O)Cl
Reactant: N#Cc1ccc(OC[C@H](O)CNC(=O)OCc2ccccc2)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CS(=O)(=O)O[C@H](CNC(=O)OCc1ccccc1)COc1ccc(C#N)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 83.8 %

Procedure:
4-(Dimethylamino)pyridine (0.22 g, 1.77 mmol) was added to a solution of benzyl (2R)-3-(4-cyanophenoxy)-2-hydroxypropylcarbamate (see step (iii) above; 5.79 g, 17.7 mmol) in pyridine (15 mL). The mixture was cooled to 0° C., and methanesulfonyl chloride (2.23 g, 19.5 mmol) was added slowly at 0° C. The mixture was allowed to reach rt, at which temperature it was then stirred for 4 h. The solvent was evaporated. DCM (100 mL) was added, washed with water, 1 N H2SO4 and brine, dried (Na2SO4) and evaporated giving 6.0 g (84%) of a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10](I)=[CH:9][N:8]([CH:12]3[CH2:21][CH2:20][C:15]4([O:19][CH2:18][CH2:17][O:16]4)[CH2:14][CH2:13]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[CH2:22]([O:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[CH2:22]([O:29][C:30]1[CH:35]=[CH:34][C:33]([C:10]2[C:3]3[C:2]([Cl:1])=[N:7][CH:6]=[N:5][C:4]=3[N:8]([CH:12]3[CH2:21][CH2:20][C:15]4([O:19][CH2:18][CH2:17][O:16]4)[CH2:14][CH2:13]3)[CH:9]=2)=[CH:32][CH:31]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: OB(O)c1ccc(OCc2ccccc2)cc1
Reactant: Clc1ncnc2c1c(I)cn2C1CCC2(CC1)OCCO2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Clc1ncnc2c1c(-c1ccc(OCc3ccccc3)cc1)cn2C1CCC2(CC1)OCCO2
Temperature: 80 °C
Reaction time: 5 h
Yield: 60.5 %

Procedure:
A mixture of 4-chloro-7-(1,4-dioxaspiro[4.5]dec-8-yl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (3.0 g, 7.15 mmol) in ethylene glycol dimethyl ether (100 mL) was treated with 4-(benzyloxy)phenylboronic acid (1.79 g, 7.87 mmol), tetrakis(triphenylphosphine)palladium (0.496 g, 0.429 mmol), and a solution of sodium carbonate (1.83 g, 17.16 mmol) in water (50 mL). A precipitate formed after 20 minutes. Reaction was stirred for 5 hours at 80° C. under a nitrogen atmosphere. The mixture was allowed to cool to room temperature and the organic solvent was removed under reduced pressure. The product was partitioned between the aqueous sodium carbonate layer and ethyl acetate. The aqueous layer was further extracted with ethyl acetate three times. The organic layers were combined, washed with water and brine, dried over magnesium sulfate, and partially concentrated until a precipitate formed. The solid was filtered, washed with ethyl acetate, and dried under a high vacuum. Yielded 2.06 g (61%) of 5-[4-(benzyloxy)phenyl]-4-chloro-7-(1,4-dioxaspiro[4.5]dec-8-yl)-7H-pyrrolo[2,3-d]pyrimidine. 1H NMR (DMSO-d6, 400 MHz) δ 8.64(s, 1H), 7.88(s, 1H), 7.52-7.33(m, 7H), 7.08-7.05(d, 2H, J=12 Hz), 5.15(s, 2H), 4.82-4.78 (m, 1H), 3.95-3.89(m, 4H), 2.21-2.13(m, 2H), 1.98-1.96(m, 2H), 1.85-1.75(m, 4H); Waters 2690 Alliance HPLC (Symmetry Shield RP18 3.5 μm, 2.1×50 mm; 5%-95% acetonitrile-0.1 M ammonium acetate over 15 min, 0.5 mL/min) Rt 8.356 min.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([N:13]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[CH:14]([CH3:16])[CH3:15])[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][N:13]([CH:14]([CH3:15])[CH3:16])[CH:10]2[CH2:11][CH2:12][NH:8][CH2:9]2)=[CH:19][CH:20]=1
Reactant: CC(C)N(Cc1ccc(Cl)cc1)C1CCN(C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)N(Cc1ccc(Cl)cc1)C1CCNC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3-[(4-chloro-benzyl)-isopropyl-amino]-pyrrolidine-1-carboxylic acid tert-butyl ester in dichloromethane cooled at 0° C. was treated with trifluoroacetic acid (20%) and warmed to room temperature and stirred for 2 hours. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate and free based with 10% aqueous sodium bicarbonate. The combined organics were dried over sodium sulfate. The product was used without any further purification. ESI-MS m/z: 253 (M+1, UV retention time: 0.59 min.