Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][C@@H:28]4[CH2:33][CH2:32][NH:31][CH2:30][C@H:29]4[OH:34])=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1.[C:35](Cl)(=[O:37])[CH3:36]>>[C:35]([N:31]1[CH2:32][CH2:33][C@@H:28]([NH:27][C:25]([C:21]2[C:17]3[N:18]=[CH:19][N:20]=[C:15]([C:8]4[CH:9]=[C:10]([O:13][CH3:14])[CH:11]=[CH:12][C:7]=4[O:6][CH2:5][CH:2]4[CH2:4][CH2:3]4)[C:16]=3[NH:23][C:22]=2[CH3:24])=[O:26])[C@H:29]([OH:34])[CH2:30]1)(=[O:37])[CH3:36]
Reactant: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@@H]4CCNC[C@H]4O)c(C)[nH]c23)c1
Reactant: CC(=O)Cl
Agent: Cl
Product: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@@H]4CCN(C(C)=O)C[C@H]4O)c(C)[nH]c23)c1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-methoxyphenyl]-N-[(3R*,4R*)-3-hydroxypiperidin-4-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f27) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13](=[O:35])[CH2:14][CH2:15][C:16]3[CH:32]=[CH:31][C:19]([O:20][C:21]([CH3:30])([CH3:29])[C:22]([O:24]C(C)(C)C)=[O:23])=[C:18]([Cl:33])[C:17]=3[Cl:34])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13](=[O:35])[CH2:14][CH2:15][C:16]3[CH:32]=[CH:31][C:19]([O:20][C:21]([CH3:30])([CH3:29])[C:22]([OH:24])=[O:23])=[C:18]([Cl:33])[C:17]=3[Cl:34])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)Oc1ccc(CCC(=O)c2ccc(-c3ccc(Br)cc3)s2)c(Cl)c1Cl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(Oc1ccc(CCC(=O)c2ccc(-c3ccc(Br)cc3)s2)c(Cl)c1Cl)C(=O)O

Procedure:
2-(4-(3-(5-(4-Bromophenyl)thien-2-yl)-3-oxopropyl)-2,3-dichlorophenoxy)-2-methylpropanoic acid is prepared from tert-butyl 2-(4-(3-(5-(4-bromophenyl)thien-2-yl)-3-oxopropyl)-2,3-dichlorophenoxy)-2-methylpropanoate according to general procedure E using 38 equivalents of trifluoroacetic acid.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[N:8]=[C:7]([C:9]2[CH:18]=[C:17]3[C:12]([CH2:13][CH2:14][N:15](C(OC(C)(C)C)=O)[CH2:16]3)=[CH:11][CH:10]=2)[CH:6]=[C:5]([N:26]2[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]2)[N:4]=1>O1CCOCC1.CO>[CH3:32][N:29]1[CH2:28][CH2:27][N:26]([C:5]2[CH:6]=[C:7]([C:9]3[CH:18]=[C:17]4[C:12]([CH2:13][CH2:14][NH:15][CH2:16]4)=[CH:11][CH:10]=3)[N:8]=[C:3]([NH2:2])[N:4]=2)[CH2:31][CH2:30]1.[ClH:1]
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)OC(C)(C)C)CC4)nc(N)n2)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6 mL of 4N HCl in dioxane was added to a solution of tert-butyl 7-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.90 g, 2.1 mmol) in methanol (5 mL). The mixture was stirred at r.t. for 2 h. The mixture was concentrated under reduced pressure. The residue was washed with ether and dried under vacuum to afford the desired product as an HCl salt (0.83 g). Analytic LCMS (M+H)+: m/z=325.4.
Reaction SMILES: [CH2:1]=[C:2]([CH3:4])[CH3:3].[CH3:5][CH:6]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:7][Cl:8].F>>[CH3:5][CH:6]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:7][Cl:8].[CH3:5][CH:6]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:2]([CH3:4])([CH3:3])[CH3:1])=[CH:12][CH:11]=1)[CH2:7][Cl:8]
Reactant: C=C(C)C
Agent: CC(CCl)Cc1ccccc1
Agent: F
Product: CC(CCl)Cc1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
20 parts by weight of isobutene are passed into a mixture of 68 parts by weight of 2-methyl-3-phenylpropyl chloride and 3 parts by weight of hydrogen fluoride at 0° C. The mixtuure is then stirred for 12 hours at room temperature. The crude product is washed with water, dried over Na2CO3 and distilled. 36 parts by weight of 2-methyl-3-phenylpropyl chloride, boiling point 105° C./16 mm Hg and 32 parts by weight of 2-methyl-3-(p-tert.-butylphenyl)-propyl chloride, boiling point 80°-81° C./0.02 mm Hg, are obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:13]2[C:14]([CH3:19])=[N:15][C:16]([Cl:18])=[CH:17][C:12]=2[N:11]([C:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Se](=O)=[O:40]>O1CCOCC1>[CH2:1]([O:8][C:9]1[C:13]2[C:14]([CH:19]=[O:40])=[N:15][C:16]([Cl:18])=[CH:17][C:12]=2[N:11]([C:20]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[Se]=O
Reactant: Cc1nc(Cl)cc2c1c(OCc1ccccc1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: O=Cc1nc(Cl)cc2c1c(OCc1ccccc1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 100 °C

Procedure:
A mixture of 3-(benzyloxy)-6-chloro-4-methyl-1-trityl-1H-pyrazolo[4,3-c]pyridine (18.72 g, 36.3 mmol) and selenium dioxide (14.42 g, 130 mmol) in dioxane (200 ml) was heated to 100° C. with attached reflux condenser for 16 hr. Added more selenium dioxide (3.35 g, 30.2 mmol) and continued to heat to 100° C. for 4.5 hr. Cooled to RT, filtered through celite, eluted with EtOAc, concentrated filtated in vacuo, took up residue in DCM, filtered through celite, eluted with DCM, concentrated filtrate in vacuo and purified via flash chromatography (0-100% EtOAc/Hex) to provide 3-(benzyloxy)-6-chloro-1-trityl-1H-pyrazolo[4,3-c]pyridine-4-carbaldehyde. MS: [M+H]+ m/z 530.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]([C:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)=[O:10])=[N:6][C:7]=1[CH3:8].[H-].[Na+].Br[CH2:25][C:26]1[N:31]=[C:30]([C:32]#[N:33])[CH:29]=[CH:28][CH:27]=1>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]([C:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:25][C:26]3[N:31]=[C:30]([C:32]#[N:33])[CH:29]=[CH:28][CH:27]=3)[CH:12]=2)=[O:10])=[N:6][C:7]=1[CH3:8]
Reactant: N#Cc1cccc(CBr)n1
Reactant: Cc1ccc(C(=O)c2c[nH]c3ccccc3c2=O)nc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)c2cn(Cc3cccc(C#N)n3)c3ccccc3c2=O)nc1C

Procedure:
Experimental conditions analogous to those described for Step 3 of Example 1, from 67 mg (0.24 mmol) of 3-(5,6-dimethyl-pyridine-2-carbonyl)-1H-quinolin-4-one, 12 mg (0.29 mmol) of 60% sodium hydride, 57 mg (0.29 mmol) of 6-bromomethyl-pyridine-2-carbonitrile and 0.7 mL of N,N-dimethylformamide. Yield: 34 mg of a white solid: LC-MSD, m/z for C24H18N4O2 [M+H]+=395.1; HPLC retention time: 1.0 min.
Reaction SMILES: CS(Cl)(=O)=O.[C:6]([O:10][C:11]([N:13]1[CH2:17][CH2:16][CH2:15][C@H:14]1[CH2:18]O)=[O:12])([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>C(Cl)Cl.C1(C)C=CC=CC=1>[C:6]([O:10][C:11]([N:13]1[CH2:17][CH2:16][CH2:15][C@H:14]1[CH2:18][N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)=[O:12])([CH3:7])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Reactant: C1COCCN1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC[C@H]1CN1CCOCC1
Temperature: 110 °C
Yield: 39.7 %

Procedure:
Methanesulfonyl chloride (1.7 g, 14.9 mmol) was added dropwise to a solution of (S)-2-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (1.5 g, 7.45 mmol) and triethylamine (753 mg mg, 7.45 mmol) in CH2Cl2 at 0° C. After 3 h reaction mixture was concentrated to give a white solid. The resulting solid was suspended in toluene, morpholine (1.3 g, 14.9 mmol) was added, and the resulting mixture was heated to 110° C. in a sealed tube. After 12 h the reaction mixture was concentrated, the resulting residue was dissolved in EtOAc and water, the layers were separated, and the aqueous was further extracted with EtOAc. The combined organic extracts were dried over Na2SO4, and the material was purified on silica gel by flash column chromatography CH2Cl2/MeOH/NH4OH (98.5/1/0.5) to afford the title compound as a white solid (800 mg, 40%). MS: 271.2 (MH+); HPLC Rf: n.d.; HPLC purity: n.d.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:16][CH:17]([CH3:19])[CH3:18])C(C=CC(O)=O)=O)=[C:4]([CH:20]([OH:35])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[O:27][CH2:28][C:29]2C=CC=CC=2)[CH:3]=1>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:16][CH:17]([CH3:18])[CH3:19])=[C:4]([CH:3]=1)[CH:20]([OH:35])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[O:27][CH2:28][CH3:29]
Reactant: CC(C)CN(C(=O)C=CC(=O)O)c1ccc(Cl)cc1C(O)c1ccccc1OCc1ccccc1
Solvent: CCO
Product: CCOc1ccccc1C(O)c1cc(Cl)ccc1NCC(C)C

Procedure:
In 150 ml of ethanol was dissolved 6.0 g of ethyl ester of 3-[N-[4chloro-2-[2-benzyloxy-α-hydroxybenzyl]phenyl]-N-isobutylcarbamoyl]acrylic acid, as obtained in (4), to which was added 3.18 g of potassium carbonate; the mixture was then stirred overnight. The solvent was distilled off under reduced pressure, and the residue was subjected to extraction with 150 ml of water and 200 ml of ethyl acetate. The ethyl acetate layer was washed with water and dried over anhydrous magnesium sulfate, then distilled off under reduced pressure. The residue was purified by means of silica gel column chromatography (eluent, hexane:ethyl acetate=5:1) to yield 5.8 g of ethyl ester of trans-5-(2-benzyloxyphenyl)-7-chloro-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid as prism crystals, m.p. 146° to 147° C.
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21](Cl)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>CN(C1C=CN=CC=1)C.CC#N>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21]([N:29]3[CH2:30][CH2:31][CH:26]([CH3:25])[CH2:27][CH2:28]3)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1CCNCC1
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCOCC1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: CC1CCN(S(=O)(=O)c2ccc3c(c2)nc(C(C)(C)C)n3CC2CCOCC2)CC1

Procedure:
Following the same procedure in Example 1, Step A, using 2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole-5-sulfonyl chloride (72 mg, 0.19 mmol), 4-methylpiperidine (0.2 mL, 168 mg, 1.69 mmol) and DMAP (69 mg, 0.61 mmol) in MeCN (5 mL). The crude product was purified by MPLC using Hex/EtOAc (1:2) on silica gel to give 38 mg (45% yield) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 0.90 (d, J=5.86 Hz, 3 H), 1.16-1.34 (m, 3 H), 1.49-1.64 (m, 4 H), 1.67 (s, 9 H), 1.67-1.73 (m, 2 H), 2.23-2.32 (m, 2 H), 2.33-2.44 (m, 1 H), 3.31-3.40 (m, 2 H), 3.73-3.82 (m, 2 H), 3.91-3.98 (m, 2 H), 4.52 (d, J=7.42 Hz, 2 H), 7.84 (dd, J=8.79, 1.76 Hz, 1 H), 8.03 (d, J=8.20 Hz, 1 H), 8.08 (d, J=1.17 Hz, 1 H); MS (ESI) (M+H)+=434.0; Anal. Calcd for C23H35N3O3S+1.10 TFA+0.40 CH3OH (571.86): C, 53.77; H, 6.65; N, 7.35. Found: C, 53.76; H, 6.69; N, 7.33.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH2:9]([O:11][C:12]1[C:21]2[C:16](=[CH:17][C:18]([CH3:22])=[CH:19][CH:20]=2)[O:15][C:14](=[O:23])[CH:13]=1)[CH3:10].N(CCCC#N)=NCCCC#N>C(Cl)(Cl)(Cl)Cl>[Br:1][CH2:22][C:18]1[CH:17]=[C:16]2[C:21]([C:12]([O:11][CH2:9][CH3:10])=[CH:13][C:14](=[O:23])[O:15]2)=[CH:20][CH:19]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOc1cc(=O)oc2cc(C)ccc12
Agent: N#CCCCN=NCCCC#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOc1cc(=O)oc2cc(CBr)ccc12
Yield: 76.7 %

Procedure:
N-Bromosuccinimide (9.59 g; 0.054 mole) was added to stirred solution of 4-ethoxy-7-methylcoumarin (11 g; 0.054 mole) in carbontetrachloride (600 ml) followed by a catalytic quantity of azo bisbutyronitrile. After refluxing the mixture for 1 hr the solvent was removed in vacuo and the residue recrystallized from ethanol to give 11.73 g (77%) of product of m.p. 150°-3° C. Further recrystallization gave material of m.p. 152°-155° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[N:14]([C:15]=2[C:16]2[CH:17]=[CH:18][C:19]4[N:20]([C:22]([C@H:25]5[CH2:30][CH2:29][C@H:28]([NH:31][C:32](=O)OC(C)(C)C)[CH2:27][CH2:26]5)=[N:23][N:24]=4)[CH:21]=2)[CH:13]=[CH:12][O:11]3)=[CH:4][CH:3]=1.CI.[H-].[Na+].C(O)(C(F)(F)F)=O>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[N:14]([C:15]=2[C:16]2[CH:17]=[CH:18][C:19]4[N:20]([C:22]([C@H:25]5[CH2:30][CH2:29][C@H:28]([NH:31][CH3:32])[CH2:27][CH2:26]5)=[N:23][N:24]=4)[CH:21]=2)[CH:13]=[CH:12][O:11]3)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](c2nnc3ccc(-c4c(-c5ccc(F)cc5)nc5occn45)cn32)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CN[C@H]1CC[C@H](c2nnc3ccc(-c4c(-c5ccc(F)cc5)nc5occn45)cn32)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a 100 mL round-bottom flask was added tert-butyl (trans)-4-(6-(6-(4-fluorophenyl)imidazo[2,1-b]oxazol-5-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)cyclohexylcarbamate (4.00 g, 7.74 mmol; Example # K.1.1.35) and MeI (0.533 mL, 8.52 mmol) which were then dissolved in THF (10 mL). NaH (0.619 g, 15.5 mmol) was added. The reaction was allowed to stir for about 16 h at ambient temperature after which time TFA (5 mL) was added. The reaction was allowed to stir at ambient temperature for about 2 h after which time the reaction was quenched with aqueous NaHCO3 and the organic layer was separated. The aqueous layer was washed with DCM and the combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography using EtOAc/MeOH (gradient, 1:0 to 9:1) to provide the title compound. (0.032 g, 1.0%): LC/MS (Table 1, Method a) Rt, =1.6 min; MS m/z: 431.2 (M+H)+.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][C:6]([CH3:32])([CH2:11][C:12](=[O:31])[NH:13][C:14]1[CH:15]=[N:16][C:17]([O:20][C:21](=[O:30])[N:22]([CH3:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:18][CH:19]=1)[CH2:7][C:8]([OH:10])=O.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>ClCCl>[CH3:5][C:6]([CH3:32])([CH2:7][C:8]([N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1)=[O:10])[CH2:11][C:12]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21](=[O:30])[N:22]([CH3:29])[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[N:16][CH:15]=1)=[O:31]
Reactant: CN(C(=O)Oc1ccc(NC(=O)CC(C)(C)CC(=O)O)cn1)c1ccccc1
Reactant: C1COCCN1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CN(C(=O)Oc1ccc(NC(=O)CC(C)(C)CC(=O)N2CCOCC2)cn1)c1ccccc1
Reaction time: 0.17 h
Yield: 63 %

Procedure:
Thionylchloride (237 microL, 3.27 mmol) was added to a stirred solution of 3,3-dimethyl-4-[6-(methyl-phenyl-carbamoyloxy)-pyridin-3-ylcarbamoyl]-butyric acid (0.63 g, 1.63 mmol) in dichloromethane (10 mL). After stirring for 10 minutes the solution was divided into 4 equal portions of acid chloride. To one portion was added morpholine (0.5 mL) and after stirring for 2 hours at room temperature the crude product was purified by flash column chromatography (SiO2), yielding the title compound (117 mg, 63% yield).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:47])[NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[N:22]=[C:21]4[N:23]([CH2:26][C:27]([F:30])([F:29])[F:28])[N:24]=[CH:25][C:20]4=[C:19]([N:31]4[CH2:38][CH:37]5[O:39][CH:33]([CH2:34][N:35](C(OC(C)(C)C)=O)[CH2:36]5)[CH2:32]4)[N:18]=3)=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.Cl>ClCCl.CO.O1CCOCC1>[CH:33]12[O:39][CH:37]([CH2:36][NH:35][CH2:34]1)[CH2:38][N:31]([C:19]1[N:18]=[C:17]([C:14]3[CH:13]=[CH:12][C:11]([NH:10][C:9]([NH:8][C:5]4[CH:4]=[CH:3][N:2]=[CH:7][CH:6]=4)=[O:47])=[CH:16][CH:15]=3)[N:22]=[C:21]3[N:23]([CH2:26][C:27]([F:29])([F:30])[F:28])[N:24]=[CH:25][C:20]=13)[CH2:32]2
Reactant: CC(C)(C)OC(=O)N1CC2CN(c3nc(-c4ccc(NC(=O)Nc5ccncc5)cc4)nc4c3cnn4CC(F)(F)F)CC(C1)O2
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C(Nc1ccncc1)Nc1ccc(-c2nc(N3CC4CNCC(C3)O4)c3cnn(CC(F)(F)F)c3n2)cc1

Procedure:
Tert-butyl 7-(6-(4-(3-pyridin-4-ylureido)phenyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate.hydrochloride (256 mg, 0.38 mmol) was dissolved in dichloromethane (20 mL) with the aid of a minimum volume of methanol. The solution was treated with 4 N hydrogen chloride in dioxane (2 mL), which caused the precipitation of a white solid within 10 minutes. The solid was collected by Buchner filtration, washed with methanol, and dried under house vacuum. A portion of the crude solid (assumed dihydrochloride) was purified by reverse-phase high performance liquid chromatography using a Phenomenex Prodigy 21 mm×250 mm column, running a gradient elution of 5% acetonitrile/95% of 0.1% aqueous trifluoroacetic acid to 65% acetonitrile to provide 1-{4-[4-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]phenyl}-3-pyridin-4-ylurea.2TFA (22 mg). MS (ES+): 540.2 (M+H)+
Reaction SMILES: [C:1](=[O:15])([O:13][CH3:14])[O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[C:5]([CH:11]=O)[CH:4]=1.C1(P(=[CH:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:10][O:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][C:1]([O:13][CH3:14])=[O:15])=[CH:4][C:5]=1[CH:11]=[CH:35][C:36]([O:38][CH2:39][CH3:40])=[O:37]
Reactant: COC(=O)Oc1ccc(OC)c(C=O)c1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C=Cc1cc(OC(=O)OC)ccc1OC
Temperature: 80 °C
Reaction time: 15 h
Yield: 90 %

Procedure:
To a solution of 3-formyl-4-methoxyphenyl methyl carbonate (10.0 g) in toluene (10 mL) was added ethyl (triphenylphosphoranylidene)acetate (21.5 g), and the mixture was stirred at 80° C. for 15 hr. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (12.0 g) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)=[CH:4][CH:3]=1.Cl.[CH3:33][C:34]1[CH:39]=[CH:38][C:37]([NH:40]N)=[CH:36][CH:35]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:40][C:37]3[C:38]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:39][C:34]([CH3:33])=[CH:35][CH:36]=3)=[CH:4][CH:3]=1
Reactant: Cc1ccc(NN)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc(F)cc3)CC2)c1
Agent: Cl
Product: Cc1ccc2[nH]c(-c3ccc(F)cc3)c(CCCN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c2c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(4-fluorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-methylphenylhydrazine hydrochloride: ESMS m/e: 512.2 (M+H)+.
Reaction SMILES: [CH2:1]1[O:39][C:38]2[CH:37]=[CH:36][C:5]([CH2:6][O:7][C:8](=[O:35])[C@H:9]([NH:20][S:21]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([O:31][CH3:32])=[C:26]([CH3:33])[C:25]=3[CH3:34])(=[O:23])=[O:22])[C@@H:10]([O:12][Si:13]([CH2:18][CH3:19])([CH2:16][CH3:17])[CH2:14][CH3:15])[CH3:11])=[CH:4][C:3]=2[O:2]1.[CH2:40]1[O:48][C:47]2[CH:46]=[CH:45][C:44]([CH2:49]O)=[CH:43][C:42]=2[O:41]1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1C=CC=CC=1>[CH2:1]1[O:39][C:38]2[CH:37]=[CH:36][C:5]([CH2:6][O:7][C:8](=[O:35])[C@H:9]([N:20]([CH2:49][C:44]3[CH:45]=[CH:46][C:47]4[O:48][CH2:40][O:41][C:42]=4[CH:43]=3)[S:21]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([O:31][CH3:32])=[C:26]([CH3:33])[C:25]=3[CH3:34])(=[O:23])=[O:22])[C@@H:10]([O:12][Si:13]([CH2:16][CH3:17])([CH2:18][CH3:19])[CH2:14][CH3:15])[CH3:11])=[CH:4][C:3]=2[O:2]1
Reactant: CC[Si](CC)(CC)O[C@@H](C)[C@@H](NS(=O)(=O)c1c(C)cc(OC)c(C)c1C)C(=O)OCc1ccc2c(c1)OCO2
Reactant: OCc1ccc2c(c1)OCO2
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: c1ccccc1
Product: CC[Si](CC)(CC)O[C@@H](C)[C@H](C(=O)OCc1ccc2c(c1)OCO2)N(Cc1ccc2c(c1)OCO2)S(=O)(=O)c1c(C)cc(OC)c(C)c1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 81.1 %

Procedure:
To a solution of 2(R)-(4-methoxy-2,3,6-trimethylbenzenesulfonyl-amino)-3(S)-(triethylsilyloxy)butyric acid 3,4-methylenedioxybenzyl ester (3.3 g, 5.7 mmol) in benzene (100 mL) at 0° C. was added 3,4-methylenedioxyphenyl methanol (1.3 g, 8.5 mmol), tri-n-butylphosphine (2.1 mL, 8.5 mmol), followed by 1,1′-[azodicarbonyl]dipiperidine (2.2 g, 8.5 mmol). The reaction mixture was allowed to warm to room temperature over 4 h. After 72 h, the reaction mixture was diluted with an equal volume of hexanes, cooled to 0° C. for 2 h and filtered. The residue was concentrated and chromatographed (300 g SiO2, 15% ethyl acetate-hexanes) to afford 2(R)-[(3,4-methylenedioxybenzyl)-(4-methoxy-2,3,6-trimethylbenzenesulfonyl)amino]-3(S)-(triethylsilyloxy)butyric acid 3,4-methylenedioxybenzyl ester (3.3 g) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH:6]=[C:5]2[S:21](Cl)(=[O:23])=[O:22].[CH3:25][NH:26][CH3:27]>C(Cl)Cl.O>[CH3:25][N:26]([CH3:27])[S:21]([C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=2)[N:7]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH:6]=1)(=[O:23])=[O:22]
Reactant: Cc1ccc(S(=O)(=O)n2cc(S(=O)(=O)Cl)c3cc(F)ccc32)cc1
Reactant: CNC
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(S(=O)(=O)N(C)C)c3cc(F)ccc32)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 99 %

Procedure:
A solution of 5-fluoro-3-chlorosulfonyl-1-(toluene-4-sulfonyl)indole (2.52 g) in DCM (75 mL) is added to an aqueous solution of dimethylamine (40%, 20 mL) in water (50 mL) and stirred at rt for 20 h. The organic phase is separated, washed with water, brine, dried (MgSO4), filtered and concentrated in vacuo to afford 5-fluoro-1-(toluene-4-sulfonyl)-1H-indole-3-sulphonic acid dimethylamide (2.55 g, 99%) as a solid. MS: 397 (M+H).
Reaction SMILES: [NH:1]1[C:7](=O)[CH2:6][CH2:5][NH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:14].O.C(OCC)(=O)C>N1C=CC=CC=1>[NH:1]1[C:7](=[S:14])[CH2:6][CH2:5][NH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2
Reactant: O=C1CCNc2ccccc2N1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: O
Product: S=C1CCNc2ccccc2N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.1 %

Procedure:
A solution of 4,5-dihydro-1H-benzo[b][1,4]diazepin-2(3H)-one (3.2 g, 19.6 mmol) and P2S5 (5.2 g, 23.5 mmol) in pyridine (100 mL) was heated at 120° C. and stirred for 30 min. After being cooled to room temperature, water (100 mL) and ethyl acetate (200 mL) were added, the separated organic layer was dried over Na2SO4, concentrated in vacuum, and the residue was purified by CombiFlash (DCM:MeOH=20:1) to give 4,5-dihydro-1H-benzo[b][1,4]diazepine-2(3H)-thione as a yellow solid (2.1 g, 59%). LRMS (M+H)+: 177 m/z.