Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:10]2[C:9]([O:11][CH3:12])=[N:8][C:7]([NH:13][CH:14]=[O:15])=[N:6][C:5]=2[N:4]([C@@H:16]2[O:26][C@H:25]([CH2:27][O:28][C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])[C@@H:18]([O:19][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])[CH2:17]2)[CH:3]=1.CC(C)C(O[C@@H]1[C@@H](COC(=O)C(C)C)O[C@@H](C2C3C(OC)=NC(NC=O)=NC=3NC=2)C1)=O.[I:66]N1C(=O)CCC1=O>C1CCCCC1>[CH3:22][CH:21]([CH3:23])[C:20]([O:19][C@@H:18]1[C@@H:25]([CH2:27][O:28][C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])[O:26][C@@H:16]([N:4]2[C:5]3[N:6]=[C:7]([NH:13][CH:14]=[O:15])[N:8]=[C:9]([O:11][CH3:12])[C:10]=3[C:2]([I:66])=[CH:3]2)[CH2:17]1)=[O:24]
Reactant: O=C1CCC(=O)N1I
Reactant: COc1nc(NC=O)nc2c1c(Cl)cn2[C@H]1C[C@H](OC(=O)C(C)C)[C@@H](COC(=O)C(C)C)O1
Agent: COc1nc(NC=O)nc2[nH]cc([C@H]3C[C@H](OC(=O)C(C)C)[C@@H](COC(=O)C(C)C)O3)c12
Solvent: C1CCCCC1
Product: COc1nc(NC=O)nc2c1c(I)cn2[C@H]1C[C@H](OC(=O)C(C)C)[C@@H](COC(=O)C(C)C)O1
Reaction time: 23 h

Procedure:
Compound (46) is prepared as described for compound (45) by proceeding from compound (18) (500 mg, 1.11 mmol) and N-iodosuccinimide (264 mg, 1.16 mmol). The duration of the reaction is 23 h. Colorless crystals (590 mg, 92%) are obtained from cyclohexane. 1H-NMR ([D6] DMSO): δ=1.9 (d, J=7.0, CH3), 1.15 (d, J=7.0, CH3), 2.46, 2.60, 2.89 (3 m, CH and Hα,β—C(2′)), 4.06 (s, OCH3), 4.17 (m, H—C(5′)), 4.27 (m, H—C(4′)), 5.35 (m, H—C(3′)), 6.46 (m, H—C(1′)), 7.62 (8, H—C(6)), 9.55 (d, J=9.7, NH), 10.81 (d, J=9.9 HCO). Anal. calculated for C21H27JN4O7 (574.4): C 43.91, H 4.74, N 9.75; found: C 43.98, H 4.75, N 9.82.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[C:19]([NH2:21])=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Br[CH2:23][C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1>>[CH3:31][O:30][C:28](=[O:29])[C:27]1[CH:32]=[CH:33][C:24]([CH2:23][N:11]([C@@H:12]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]2[C:19](=[O:20])[NH2:21])[S:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)(=[O:9])=[O:10])=[CH:25][CH:26]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: NC(=O)[C@@H]1CCCCC[C@@H]1NS(=O)(=O)c1ccc(Cl)cc1
Product: COC(=O)c1ccc(CN([C@@H]2CCCCC[C@@H]2C(N)=O)S(=O)(=O)c2ccc(Cl)cc2)cc1
Yield: 28 %

Procedure:
The titled compound (321 mg) was prepared in 28% yield from cis-2-(4-chlorobenzenesulfonylamino)-cycloheptanecarboxylic acid amide (800 mg, 2.42 mmol) and methyl 4-(bromomethyl)benzoate according to the N-alkylation procedure described in Example 11: 1H NMR (DMSO-d6) δ 7.83 (m, 4 H), 7.65 (d, 2 H,J=8.0 Hz), 7.45 (d, 2 H, J=12.0 Hz), 7.31 (s br, 1 H), 6.64 (s br, 1 H), 4.60 (AB2,2 H,Δv=16,Jab=92 Hz), 3.96 (m, 1 H), 3.85 (m, 3 H), 2.78 (m, 1 H), 2.28 (m, 1 H), 1.72 (m, 2 H), 1.35 (m, 7 H); MS m/e 479.12 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:15][CH2:16][CH3:17])([CH2:12][CH2:13][CH3:14])[C:4](=[O:18])[C:3]=1C(OCC)=O.C(C1(CCCC)C2C(=CC=CC=2)C(O)=C(C(OCC)=O)C1=O)CCC>>[CH2:15]([C:5]1([CH2:12][CH2:13][CH3:14])[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([OH:1])=[CH:3][C:4]1=[O:18])[CH2:16][CH3:17]
Reactant: CCCC1(CCC)C(=O)C(C(=O)OCC)=C(O)c2ccccc21
Agent: CCCCC1(CCCC)C(=O)C(C(=O)OCC)=C(O)c2ccccc21
Product: CCCC1(CCC)C(=O)C=C(O)c2ccccc21

Procedure:
The title compound was prepared according the procedure of Example 5B, substituting the product of Example 1F for the product of Example 4F. 1H NMR (300 MHz, CDCl3) δ ppm 0.55 (m, 2H) 0.67 (m, 4.8H) 0.79 (m, 1.2H) 0.98 (m, 2H) 1.78 (m, 2H) 2.19 (m, 2H) 3.69 (s, 0.4H) 6.13 (s, 0.8H) 7.41 (m, 2H) 7.56 (m, 0.8H) 7.67 (m, 0.2H) 8.07 (m, 0.2H) 8.13 (m, 0.8H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:29][CH2:30][CH2:31]CS([O-])(=O)=O)[CH2:13][C:12](=[O:14])[N:11]([C:15](=[O:28])[C:16]3[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[C:38]1([C:44]2([C:50]([NH2:52])=[O:51])[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:29][CH2:30][CH2:31][N:47]3[CH2:46][CH2:45][C:44]([C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)([C:50]([NH2:52])=[O:51])[CH2:49][CH2:48]3)[CH2:13][C:12](=[O:14])[N:11]([C:15](=[O:28])[C:16]3[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1cc(C(=O)N2CC(CCCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)CC2=O)cc(OC)c1OC
Reactant: NC(=O)C1(c2ccccc2)CCNCC1
Agent: Cl
Product: COc1cc(C(=O)N2CC(CCCN3CCC(C(N)=O)(c4ccccc4)CC3)(c3ccc(Cl)c(Cl)c3)CC2=O)cc(OC)c1OC

Procedure:
Prepare according to the method of example 3.3 using 3-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-5-oxo-pyrrolidin-3-yl]-propyl-methanesulfonate (5 mmol) and 4-phenyl-piperidine-4-carboxylic acid amide hydrochloride (7.5 mmol, 1.5 eq.). Chromatograph on silica gel to give the title compound.
Reaction SMILES: [P:1]([O:13][CH2:14][CH2:15][CH2:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]([CH3:27])[CH:22]=[C:21]([C:28]([NH:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)=[O:29])[C:20]2=[O:39])([O:8]C(C)(C)C)([O:3]C(C)(C)C)=[O:2]>C(O)(C(F)(F)F)=O.ClCCl>[P:1]([OH:8])([OH:3])([O:13][CH2:14][CH2:15][CH2:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]([CH3:27])[CH:22]=[C:21]([C:28]([NH:30][CH2:31][C:32]1[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][CH:37]=1)=[O:29])[C:20]2=[O:39])=[O:2]
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CCCOP(=O)(OC(C)(C)C)OC(C)(C)C)ccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CCCOP(=O)(O)O)ccc21
Yield: 106.9 %

Procedure:
A solution of 77.8 mg of di(tert-butyl) 3-(3-{[(4-chlorobenzyl)amino]carbonyl}-1-methyl-4-oxo-1,4-dihydro-6-quinolinyl)propyl phosphate from Example No. 32 in 1 mL of 1:1 TFA-dichloromethane is stirred for 1 h, then added slowly to 20 mL of rapidly stirred 1:1 ether-hexane. The precipitated solid is filtered, washed with hexane, and dried under vacuum to afford 67 mg of the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7](=[N:17][OH:18])[NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([Cl:16])[CH:10]=2)=[N:4][O:5][N:6]=1.[C:19](N1C=CN=C1)(N1C=CN=C1)=[O:20]>O1CCCC1>[NH2:1][C:2]1[C:3]([C:7]2[N:8]([C:9]3[CH:14]=[CH:13][C:12]([F:15])=[C:11]([Cl:16])[CH:10]=3)[C:19](=[O:20])[O:18][N:17]=2)=[N:4][O:5][N:6]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1nonc1C(=NO)Nc1ccc(F)c(Cl)c1
Solvent: C1CCOC1
Product: Nc1nonc1-c1noc(=O)n1-c1ccc(F)c(Cl)c1
Temperature: 25 °C
Yield: 102 %

Procedure:
A solution of 4-amino-N-(3-chloro-4-fluorophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide (80 g, 0.29 mol) [see US Pat. App. Pub. No. 2006/0258719] in tetrahydrofuran (500 mL) was treated with a solution of 1,1′-carbonyldiimidazole (53 g, 0.32 mol) in tetrahydrofuran (200 mL) and heated at reflux for 1 h. The reaction mixture was cooled to 25° C. and concentrated to the point where a large amount of solid precipitated. The heterogeneous mixture was diluted with ethyl acetate (1.5 L) and washed with 1 N HCl (2×300 mL), water (300 mL), and brine (200 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and concentrated to give the desired product (88 g, quantitative) as an off-white solid. This material was used without further purification. LCMS for C10H6ClFN5O3 (M+H)+: m/z=298.0. 1H NMR (400 MHz, DMSO-d6): δ 7.96 (dd, J=6.6, 2.3 Hz, 1H), 7.69-7.60 (m, 2H), 6.60 (s, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[CH2:11][C:10]([CH3:14])=[N:9]2)=[CH:4][CH:3]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:27]=[CH:28]B(O)O)[CH:20]=[CH:21][C:22]=1[O:23][CH2:24][O:25][CH3:26].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:27]=[CH:28][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[C:12](=[O:13])[CH2:11][C:10]([CH3:14])=[N:9]3)=[CH:4][CH:3]=2)[CH:20]=[CH:21][C:22]=1[O:23][CH2:24][O:25][CH3:26]
Reactant: COCOc1ccc(C=CB(O)O)cc1OC
Reactant: CC1=NN(c2ccc(Br)cc2)C(=O)C1
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
Product: COCOc1ccc(C=Cc2ccc(N3N=C(C)CC3=O)cc2)cc1OC
Reaction time: 0.17 h
Yield: 101.1 %

Procedure:
2-(4-Bromo-phenyl)-5-methyl-2,4-dihydro-pyrazol-3-one (105 mg) was dissolved in DME (ethylene glycol dimethyl ether, 2 mL), then Pd(PPh3)4 (15 mg, 3% mol) was added. The air was exchanged with argon and the mixture was stirred for 10 min. A solution of 2-(3-methoxy-4-methoxymethoxy-phenyl)-vinyl-boronic acid (90 mg) in DME (1 mL) was added followed by sodium carbonate solution (2M, 0.75 mL). The mixture was stirred for 1 hour at 110° C. After partitioning with ethyl acetate and water and purification over silica gel eluting with 50% EtOAc in hexane gave 140 mg of 2-{4-[2-(3-methoxy-4-methoxymethoxy-phenyl)-vinyl]-phenyl}-5-methyl-2,4-dihydro-pyrazol-3-one as an oily product, which was then hydrolyzed with conc. HCl in methanol. Evaporation of the solvent and purification over silica gel gave 2-{4-[2-(4-hydroxy-3-methoxy-phenyl)-vinyl]-phenyl}-5-methyl-2,4-dihydro -pyrazol-3-one as a light yellow solid (90 mg). 1HNMR (CDCl3, 300 MHz): 7.74 (d, J=8.6 Hz, 2H), 7.30 (d, J=8.6 Hz, 2H), 6.77 (s, 3H), 6.48 (s 2H), 5.66 (s, 1H), 3.63 (s, 3H), 3.42 (s, 2H), 2.19(s, 3H) ppm. 13CNMR (CDCl3—CD3OD, 75 MHz): 170.48, 156.45, 146.04, 144.89, 136.70, 134.28, 129.97, 129.41, 128.00, 122.47, 118.46, 114.21, 111.14, 55.72, 43.10, 17.05 ppm. MS (m/z): 323 (MH+).
Reaction SMILES: [C:1]([C@H:5]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[N:6]1[S:19]([C:22]1[CH:27]=[CH:26][C:25]([O:28]C)=[CH:24][CH:23]=1)(=[O:21])=[O:20])([CH3:4])([CH3:3])[CH3:2].C1CCCCC=1.B(Br)(Br)Br.ClCCl>>[C:1]([C@H:5]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[N:6]1[S:19]([C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)(=[O:21])=[O:20])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(S(=O)(=O)N2c3ccccc3-c3ccccc3[C@@H]2C(C)(C)C)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: C1=CCCCC1
Product: CC(C)(C)[C@H]1c2ccccc2-c2ccccc2N1S(=O)(=O)c1ccc(O)cc1

Procedure:
The title compound was prepared from (S)-6-tert-butyl-5-[(4-methoxyphenyl)sulfonyl]-5,6-dihydrophenanthridine (1.35 g, 3.31 mmol), cyclohexene (6.16 g, 75 mmol), and 1.0 M boron tribromide in dichloromethane (20 mL, 20 mmol) according to the procedure and in the same manner as described in Example 12, step b; and yielded, after chromatographic purification and crystallization from a mixture of diethyl ether-hexane, 4-{[(S)-6-tert-butylphenanthridin-5(6H)-yl]sulfonyl}phenol* (0.975 g, 2.48 mmol, 75%) as a homogeneous, colorless, crystalline (prisms), single enantiomer*, m.p. 187-189° C.;
Reaction SMILES: [C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:21][C:22]([N:24]4[CH2:29][CH2:28][CH:27]([CH2:30][O:31]C5CCCCO5)[CH2:26][CH2:25]4)=[O:23])[CH:17]=3)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CO.O>[C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:21][C:22]([N:24]4[CH2:29][CH2:28][CH:27]([CH2:30][OH:31])[CH2:26][CH2:25]4)=[O:23])[CH:17]=3)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=C(Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1)N1CCC(COC2CCCCO2)CC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CO
Product: O=C(Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1)N1CCC(CO)CC1
Temperature: 55 °C
Reaction time: 1 h
Yield: 60.1 %

Procedure:
4-(Tetrahydro-pyran-2-yloxymethyl)-piperidine-1-carboxylic acid [2-((R)-indan-1-ylamino)-quinolin-6-yl]-amide (0.070 g) was dissolved in methanol (1 mL). Pyridinium toluene-4-sulfonate (11.0 mg) was added and the reaction mixture stirred at 55° C. for 1 h. The reaction mixtures was diluted with water and extracted with ethyl acetate. The combined organic phases were dried on sodium sulfate, evaporated and the residue was subjected to column chromatography (silica gel, dichloro methane:methanol gradient=100:0→90:10) to yield the title compound (35 mg; 60%) as an off-white solid; MS: m/e=416.7 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.C[O:12][C:13]1[CH:18]=CC=C[C:14]=1C=CC(=O)C>>[Br:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[CH:14][C:13](=[O:12])[CH3:18]
Reactant: O=Cc1ccc(F)cc1Br
Reactant: COc1ccccc1C=CC(C)=O
Product: CC(=O)C=Cc1ccc(F)cc1Br

Procedure:
The title compound was prepared from 2-bromo-4-fluoro-benzaldehyde (30 g, 148 mmol), following the procedure describing the synthesis of 4-(2-methoxy-phenyl)-but-3-en-2-one (example 1/a stage 1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[CH:10]=[CH:11][C:7]=2[C:6]([C:20]#[N:21])=[CH:5][N:4]=1.C1C(=O)N([Br:29])C(=O)C1>C(OCC)(=O)C>[Br:29][C:11]1[C:7]2[C:6]([C:20]#[N:21])=[CH:5][N:4]=[C:3]([O:2][CH3:1])[C:8]=2[N:9]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:17])([CH3:19])[CH3:18])[CH:10]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ncc(C#N)c2ccn(COCC[Si](C)(C)C)c12
Solvent: CCOC(C)=O
Product: COc1ncc(C#N)c2c(Br)cn(COCC[Si](C)(C)C)c12
Temperature: 60 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
To a solution of 7-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridine-4-carbonitrile (1.34 g) in ethyl acetate (20.15 mL) was added NBS (1.97 g) at room temperature, and the mixture was stirred at 60° C. for 2 hr. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.30 g).
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[C:9]3[C:5]([CH:6]=[CH:7][NH:8]3)=[CH:4][C:3]=2[O:2]1.O1CCCC1.C([Li])CCC.[C:23]1([S:29](Cl)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl.O.C(Cl)Cl>[CH2:1]1[O:12][C:11]2[CH:10]=[C:9]3[C:5]([CH:6]=[CH:7][N:8]3[S:29]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)(=[O:31])=[O:30])=[CH:4][C:3]=2[O:2]1
Reactant: c1cc2cc3c(cc2[nH]1)OCO3
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: O=S(=O)(c1ccccc1)n1ccc2cc3c(cc21)OCO3
Temperature: 25 °C
Yield: 109.4 %

Procedure:
To a solution of 5,6-methylenedioxyindole (11.5 gm, 71 mmol) in freshly distilled tetrahydrofuran (60 ml) under a nitrogen atomosphere at -70° C. was added dropwise 1.6M n-butyllithium (50 ml, 80 mmol) over a one-half hour period. Then benzenesulfonyl chloride (10.5 ml, 82 mmol) was added dropwise. The reaction mixture was gradually warmed to room temperature and poured into water/methylene chloride The methlene chloride layer was separated, dried (anhydrous Na2So4), filtered and evaporated to give 23.4 gm of crude product. This solid was triturated with diethyl ether and the purified product collected by filtration (18.0 gm), mp 142°-145° C.
Reaction SMILES: CC1C=CC(N2CCN(C)CC2)=CC=1N.CN1CCNCC1.CC1C=CC(N2CCOCC2)=CC=1N.COC1C=CC(CN(CC2C=CC(OC)=CC=2)C2N=CC(C3C4CCNC=4N=C(N4CCOCC4)N=3)=CN=2)=CC=1.[CH3:77][C:78]1[CH:83]=[CH:82][C:81]([N:84]2[CH2:89][CH2:88][N:87]([CH3:90])[CH2:86][CH2:85]2)=[CH:80][C:79]=1[NH:91][C:92]([N:94]1[C:98]2[N:99]=[C:100]([N:128]3[CH2:133][CH2:132][O:131][CH2:130][CH2:129]3)[N:101]=[C:102]([C:103]3[CH:104]=[N:105][C:106]([N:109](CC4C=CC(OC)=CC=4)CC4C=CC(OC)=CC=4)=[N:107][CH:108]=3)[C:97]=2[CH2:96][CH2:95]1)=[O:93]>>[CH3:77][C:78]1[CH:83]=[CH:82][C:81]([N:84]2[CH2:89][CH2:88][N:87]([CH3:90])[CH2:86][CH2:85]2)=[CH:80][C:79]=1[NH:91][C:92]([N:94]1[C:98]2[N:99]=[C:100]([N:128]3[CH2:133][CH2:132][O:131][CH2:130][CH2:129]3)[N:101]=[C:102]([C:103]3[CH:104]=[N:105][C:106]([NH2:109])=[N:107][CH:108]=3)[C:97]=2[CH2:96][CH2:95]1)=[O:93]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4C(=O)Nc3cc(N4CCN(C)CC4)ccc3C)cn2)cc1
Agent: CN1CCNCC1
Agent: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Agent: Cc1ccc(N2CCN(C)CC2)cc1N
Product: Cc1ccc(N2CCN(C)CC2)cc1NC(=O)N1CCc2c(-c3cnc(N)nc3)nc(N3CCOCC3)nc21
Yield: 56 %

Procedure:
Using 2-methyl-5-(4-methyl-piperazin-1-yl)-phenylamine (69 mg) obtained using 1-methyl-piperazine instead of morpholine in the same manner as Step A and Step B in Example 1-D-237, instead of 2-methyl-5-morpholin-4-yl-phenylamine, from bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (150 mg), in the same manner as Step C in Example 1-D-237, 4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid [2-methyl-5-(4-methyl-piperazin-1-yl)-phenyl]-amide was obtained as a crude product. The PMB groups were removed according to Deprotection method 2, to obtain the desired compound (D-238) as an ivory solid (82 mg, 56%).
Reaction SMILES: [CH:1]12[CH2:12][CH:7]([CH:8](O)[CH:9]1O)[CH:6]1[CH:2]2[CH:3]=[CH:4][CH2:5]1.I([O-])(=O)(=O)=O.[Na+].[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.ClC(Cl)C>[C:20]1([CH2:19][N:26]2[CH2:9][CH:1]3[CH2:12][CH:7]([CH:6]4[CH:2]3[CH:3]=[CH:4][CH2:5]4)[CH2:8]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: OC1C(O)C2CC1C1C=CCC12
Reactant: NCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CC(Cl)Cl
Solvent: O
Product: C1=CC2C3CC(CN(Cc4ccccc4)C3)C2C1
Reaction time: 0.75 h
Yield: 75.4 %

Procedure:
To a stirred solution of tricyclo[5.2.1.02,6]dec-3-ene-8,9-diol (Preparation 36, 6.24 g, 37.6 mmol) in dioxane (100 ml) was added sodium periodate (8.04 g, 37.6 mmol) in water (80 ml) and the reaction mixture was stirred vigorously for 45 min. The reaction mixture was extracted with ethyl acetate (4×100 ml) and the combined extracts were washed with brine, dried (Na2SO4) and concentrated in vacuo. The crude oil (6.1 g, 37.1 mmol) was diluted with dichloroethane (400 ml) and benzylamine (3.98 g, 37.1 mmol) was added. After 3 min, sodium triacetoxyborohydride (25.23 g, 119 mmol) was added and the reaction mixture was stirred at room temperature for 18 h. Saturated sodium carbonate solution (200 ml) was added, and after 30 min, the layers were separated and the aqueous layer was washed with dichloromethane (3×50 ml). The combined organic extracts were washed with brine, filtered and concentrated. The crude yellow oil was purified by flash chromatography eluting with ethyl acetate:dichloromethane (10:90) to give the title compound as a colourless oil (6.7 g, 75%)
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[O:9]([C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C(O)C.C1(C)C=CC=CC=1>[Br:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[O:9][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:7]=1
Reactant: Brc1cncc(Br)c1
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
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: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: Brc1cncc(-c2ccccc2Oc2ccccc2)c1
Temperature: 25 °C
Yield: 32.3 %

Procedure:
Under a nitrogen atmosphere, a mixture of 3,5-dibromopyridine (5.16 g, 21.8 mmol), water (36.5 mL), toluene (145 mL), ethanol (36.5 mL), 4-phenoxyphenylboronic acid (5.00 g, 23.3 mmol), sodium carbonate (4.9 g, 47 mmol) and tetrakis(triphenylphosphine)palladium (1.25 g, 1.04 mmol) was stirred and heated under reflux for 5 h. After cooling to room temperature, water (150 mL) was added and the aqueous phase separated and extracted with ethyl acetate (3×100 mL). The combined organic phases were washed with water (50 mL), then dried (MgSO4), treated with 3S Black (decolorizing charcoal), filtered, and concentrated by rotary evaporation. The residue was purified by column chromatography, eluting with cyclohexane/ethyl acetate (90/10, v/v) to give 2.3 g (32%) of a white solid, mp 109° C.
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7]2[C:12]([CH3:13])=[CH:11][N:10]=[C:9]([NH:14][C:15](=[O:17])[CH3:16])[CH:8]=2)=[CH:4][C:3]=1[C:18]1[N:22]=[CH:21][NH:20][N:19]=1.CCN(C(C)C)C(C)C.[CH3:32][Si:33]([CH2:36][CH2:37][O:38][CH2:39]Cl)([CH3:35])[CH3:34]>CN(C=O)C.O>[Br:1][C:2]1[O:6][C:5]([C:7]2[C:12]([CH3:13])=[CH:11][N:10]=[C:9]([NH:14][C:15](=[O:17])[CH3:16])[CH:8]=2)=[CH:4][C:3]=1[C:18]1[N:22]=[CH:21][N:20]([CH2:39][O:38][CH2:37][CH2:36][Si:33]([CH3:35])([CH3:34])[CH3:32])[N:19]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: CC(=O)Nc1cc(-c2cc(-c3nc[nH]n3)c(Br)o2)c(C)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Nc1cc(-c2cc(-c3ncn(COCC[Si](C)(C)C)n3)c(Br)o2)c(C)cn1
Temperature: 0 °C
Yield: 13.5 %

Procedure:
A solution of N-{4-[5-bromo-4-(1H-1,2,4-triazol-3-yl)-2-furyl]-5-methylpyridin-2-yl}acetamide (6.0 g, 16.6 mmol) in dry DMF (150 mL) was allowed to stir at 0° C. To this cooled solution was added DIEA (6.5 g, 5.0 mmol) portionwise over 20 min under an atmosphere of nitrogen. The reaction mixture was allowed to stir for 10 min at 0° C. and then SEM-Cl (5.5 g, 33.2 mmol) in dry DMF was add dropwise over 10 min. The reaction mixture was allowed to stir at 0° C. for 10 min and then allowed to warm to rt and allowed to stir for 3 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic solutions were combined, washed with water and brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to give N-{4-[5-bromo-4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-2-furyl]-5-methylpyridin-2-yl}acetamide (1.1 g, 21%) plus an additional SEM regioisomer (1.7 g, 25%).
Reaction SMILES: C([O:5][C:6](=[O:15])[CH2:7][O:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)(C)(C)C.Cl>O1CCOCC1>[N:11]1[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:7][C:6]([OH:15])=[O:5])[CH:10]=1
Reactant: CC(C)(C)OC(=O)COc1cccnc1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)COc1cccnc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of (Pyridin-3-yloxy)-acetic acid tert-butyl ester (60 mg, 0.29 mmol) and HCl in dioxane (4 M, 2 mL) is stirred at room temperature for 1 h. The reaction mixture is concentrated in vacuo to give the title compound. MS: 154 [M+H]+; tR (HPLC, ACQUITY UPLC™ BEH C18 1.7 μm, 50×2.1 mm; 5% CH3CN+0.1% TFA/H2O+0.1% TFA for 0.5 min then 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 5 min then 100% CH3CN+0.1% TFA for 1.5 min, flow 0.5 ml/min): 0.40 min.