Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH:4][CH2:5][C@H:6]1[CH2:10][CH2:9][CH2:8][NH:7]1)([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[Br:20][C:21]1[CH:22]=[C:23]([C:27]2[C:28](=[O:41])[N:29]([CH3:40])[C:30](Cl)=[N:31][C:32]=2[C:33]2[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=2)[CH:24]=[CH:25][CH:26]=1>ClCCl>[Br:20][C:21]1[CH:22]=[C:23]([C:27]2[C:28](=[O:41])[N:29]([CH3:40])[C:30]([N:7]3[CH2:8][CH2:9][CH2:10][CH:6]3[CH2:5][NH:4][CH:1]([CH3:3])[CH3:2])=[N:31][C:32]=2[C:33]2[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=2)[CH:24]=[CH:25][CH:26]=1
Reactant: Cn1c(Cl)nc(-c2ccncc2)c(-c2cccc(Br)c2)c1=O
Reactant: CC(C)NC[C@H]1CCCN1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)NCC1CCCN1c1nc(-c2ccncc2)c(-c2cccc(Br)c2)c(=O)n1C
Reaction time: 0.17 h

Procedure:
To a 100 mL RBF, was added (R)-isopropyl-pyrrolidin-2-ylmethyl-amine (0.78 g, 3.6 mmol), and 50 mL dichloromethane at 0° C. under nitrogen. 2.1 mL diisopropylethylamine (12 mmol) was added drop wise, and stirred for 10 min. 5-(3-Bromo-phenyl)-2-chloro-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one (1.13 g, 3 mmol) was added in one portion. The mixture was stirred at 0° C. to rt for 12 h. The mixture was diluted with 100 mL dichloromethane, washed with sat. NaHCO3 and brine. After purified by flash chromatography, the title compound was yielded in 1.3 g as pale yellow solid. MS (ES+): 482 (M+H)+.
Reaction SMILES: [CH:1]([N:4]([P:8]([N:10]([CH:14]([CH3:16])[CH3:15])[CH:11]([CH3:13])[CH3:12])Cl)[CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:24][CH:25]([OH:27])[CH3:26]>C(OCC)C>[CH:25]([O:27][P:8]([N:10]([CH:14]([CH3:16])[CH3:15])[CH:11]([CH3:13])[CH3:12])[N:4]([CH:5]([CH3:7])[CH3:6])[CH:1]([CH3:3])[CH3:2])([CH3:26])[CH3:24]
Reactant: CC(C)O
Reactant: CC(C)N(C(C)C)P(Cl)N(C(C)C)C(C)C
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(C)OP(N(C(C)C)C(C)C)N(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 5.5 h

Procedure:
Bis(diisopropylamino)chlorophosphine (19, 250.1 g, 937 mmol) was dissolved in anhydrous ethyl ether (3.6 L) and triethylamine (190 g, 1.87 mol) was introduced. The turbid mixture was cooled at 0° C. and a solution of 2-propanol (225 g, 287 mL) in ether (200 mL) was added via a funnel. The resulting cloudy mixture was stirred at room temperature for 5.5 hours. The reaction was complete by checking with 31P NMR (δ=116.10 ppm, S). White solid (triethylamine HCl salt) was removed by filtration. The filtrate was concentrated to furnish a pale brown liquid (272 g, quantitative) and used for next step without further purification. Note that the P(III)-reagent can be purified by vacuum distillation (bp 84-86° C., 5 mm Hg) if desired to furnish a colorless clear oil. 1H NMR (CDCl3): δ 3.91 (m, 1H), 3.51 (m, 4 H), 1.19 (d, 6 H, J=6 Hz), 1.16 (24 H, m). 31P NMR (CDCl3): δ 116.1.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]1[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[CH:10][N:9]=1.[CH2:25]([OH:34])[CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][OH:33].O>CN(C=O)C>[OH:34][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][C:8]1[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[CH:10][N:9]=1
Reactant: O=[N+]([O-])c1ccc(/C=C/c2ccc(Cl)nc2)cc1
Reactant: OCCOCCOCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(/C=C/c2ccc(OCCOCCOCCO)nc2)cc1
Temperature: 25 °C
Yield: 77.3 %

Procedure:
The mixture of potassium carbonate (158.7 mg, 1.15 mmol), compound 3 (100 mg, 0.38 mmol) and triethylene glycol (576 mg, 3.8 mmol) in anhydrous DMF (5.0 ml) was sealed in a microwavable vial (from Biotage) and subjected to microwave irradiation (Biotage Initiator system) at 180° C. for 25 min. After cooling to room temperature, water was added and reaction mixture was extracted with ethyl acetate. Organic layer was separated, washed with brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified with PTLC (4% MeOH in DCM as developing solvent) gave product 7 (110 mg, Yield: 77%): 1H NMR (200 MHz, CDCl3): δ.8.20 (3H, m), 7.83 (1H, d, d, J1=8.6 Hz, J2=2.4 Hz), 7.61 (2H, d, J=8.8 Hz), 7.10 (2H, m) 6.84 (1H, d, J=8.6 Hz), 4.53 (2H, t, J=4.8 Hz), 3.88 (2H, t, J=4.8 Hz), 3.71 (6H, m), 3.61 (2H, m), 2.10 (1H, b), HRMS (EI) m/z calcd. for [C19H22N2O6]+ 374.1478.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C@@H:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C@H:6]1[OH:15])[CH3:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:35][O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1O>C1C=CC=CC=1>[CH3:35][O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[O:15][C@@H:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:13][CH2:14][C@H:5]1[CH2:4][N:2]([CH3:1])[CH3:3]
Reactant: CN(C)C[C@@H]1CCc2ccccc2[C@H]1O
Reactant: COc1ccccc1O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: COc1ccccc1O[C@@H]1c2ccccc2CC[C@H]1CN(C)C
Reaction time: 2 h

Procedure:
A mixture of 8.21 g (0.04M) of TRANS-1,2,3,4-tetrahydro-2-(N,N-dimethylaminomethyl)naphthalen-1-ol, 11.54 g (0.044M) of triphenyl phosphine, 5.46 g (0.044M) of 2-methoxyphenol and 100 ml of benzene was stirred and a solution of 7.83 g (0.004M) of 95% diethyl azodicatrboxylate in 25 ml of benzene was added dropwise over 45 minutes. After 2 hours, the mixture was filtered and extracted with cold 3% hydrochloric acid. The acid extracts were made basic with dilute sodium hydroxide and the oil which separated was extracted into ether. The solvent was removed and the residual oil chromatographed on silica gel.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH:16]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([N:7]2[C:8]3[C:4](=[CH:3][C:2]([F:1])=[CH:10][CH:9]=3)[C:5]([C:11]3[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH:16]=3)=[CH:6]2)(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: CN1CC=C(c2c[nH]c3ccc(F)cc23)CC1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Product: CN1CC=C(c2cn(S(=O)(=O)c3ccc(Cl)cc3)c3ccc(F)cc23)CC1

Procedure:
(28.1 mg, 53%), from 5-fluoro-3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (Example 4b, 30.1 mg, 0.131 mmol) and 4-chlorophenylsulfonyl chloride (55.3 mg, 0.26 mmol); HRMS-FAB+ for C20H19N2O2SClF calculated MH+ : 405.08998; found: 405.08291.
Reaction SMILES: [F:1][C:2]([F:25])([C:6]([F:24])([F:23])[C:7]([F:22])([F:21])[C:8]([F:20])([F:19])[C:9]([F:18])([F:17])[C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12])[C:3](Cl)=[O:4].[OH:26][C:27]1[CH:69]=[CH:68][C:30]([C:31]2[CH:36]=[CH:35][C:34]([C:37]3[C:50]4[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=4)[C:44]4[CH:43]=[CH:42][C:41]([C:62]5[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=5)([C:51]5[CH:56]=[CH:55][C:54]([N:57]6[CH2:61][CH2:60][CH2:59][CH2:58]6)=[CH:53][CH:52]=5)[O:40][C:39]=4[CH:38]=3)=[CH:33][CH:32]=2)=[CH:29][CH:28]=1.N1C=CC=CC=1.Cl>C(Cl)Cl>[F:1][C:2]([F:25])([C:6]([F:24])([F:23])[C:7]([F:22])([F:21])[C:8]([F:20])([F:19])[C:9]([F:18])([F:17])[C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12])[C:3]([O:26][C:27]1[CH:28]=[CH:29][C:30]([C:31]2[CH:32]=[CH:33][C:34]([C:37]3[C:50]4[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=4)[C:44]4[CH:43]=[CH:42][C:41]([C:62]5[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=5)([C:51]5[CH:56]=[CH:55][C:54]([N:57]6[CH2:61][CH2:60][CH2:59][CH2:58]6)=[CH:53][CH:52]=5)[O:40][C:39]=4[CH:38]=3)=[CH:35][CH:36]=2)=[CH:68][CH:69]=1)=[O:4]
Reactant: O=C(Cl)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: Oc1ccc(-c2ccc(-c3cc4c(c5ccccc35)C=CC(c3ccccc3)(c3ccc(N5CCCC5)cc3)O4)cc2)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Oc1ccc(-c2ccc(-c3cc4c(c5ccccc35)C=CC(c3ccccc3)(c3ccc(N5CCCC5)cc3)O4)cc2)cc1)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Yield: 25.1 %

Procedure:
2,2,3,3,4,4,5,5,6,6,7,7,8,8,8-Pentadecafluoro-octanoyl chloride (0.30 g, 0.7 mmol) was added to a solution of 6-[4′-(hydroxy)biphen-4-yl]-3-phenyl-3-(4-pyrrolidinophenyl)-3H-naphtho[2,1-b]pyran (0.40 g, 0.7 mmol) in DCM (30 mL) containing pyridine (2 mL) under N2 at 0° C. with stirring. The mixture was stirred at room temperature for 1 h, poured into HCl (2 M, 100 mL), extracted with DCM (3×50 mL), washed with water (100 mL), dried (MgSO4) and the solvent removed under reduced pressure. The residue was filtered through a short plug of silica using DCM (60% in hexanes) as eluent and the solvent removed under reduced pressure. The residue was dissolved in Et2O, hexane was added and the solvent reduced. The resulting precipitate was filtered to give the title compound (0.17 g, 25%) as a colourless powder, mp 144-145° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][N:3]=1.O.[NH2:12][NH2:13]>O1CCOCC1>[NH:12]([C:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][N:3]=1)[NH2:13]
Reactant: O=C(O)c1ccnc(Cl)c1
Reactant: NN
Solvent: C1COCCO1
Solvent: O
Product: NNc1cc(C(=O)O)ccn1
Temperature: 100 °C
Yield: 4.2 %

Procedure:
To a solution of 2-chloropyridine-4-carboxylic acid (1.57 g, 100 mmol) in 1,4-dioxane (30 mL) was added hydrazine hydrate (1.0 g, 200 mmol) dropwise at rt. The reaction mixture was heated at 100° C. overnight. The mixture was concentrated, and the residue was purified by flash column chromatography (CH2Cl2/MeOH=20/1) to afford the title compound (650 mg, 42%) as a white solid. [M+H] Calc'd for C6H7N3O2, 154; Found, 154.
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[NH:13]1[CH2:18][CH2:17][CH:16]([C:19]#[N:20])[CH2:15][CH2:14]1>>[C:1]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]#[N:20])[CH2:15][CH2:14]1)(=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: N#CC1CCNCC1
Reactant: CCCCCCC/C=C/C(=O)O
Product: CCCCCCC/C=C/C(=O)N1CCC(C#N)CC1

Procedure:
The same procedures as in Example 2 were carried out using (E)-2-decenoic acid and piperidine-4-carbonitrile as starting raw materials, to produce an intended compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[CH:9][C:10]=1[CH3:11])=[O:5])[CH3:2].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH2:20][C:21](Cl)=[O:22])[CH:17]=[CH:18][CH:19]=1>>[CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]([C:21](=[O:22])[CH2:20][C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([O:13][CH3:12])[CH:15]=2)[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: COc1cccc(CC(=O)Cl)c1
Reactant: CCOC(=O)c1[nH]ccc1C
Product: CCOC(=O)c1[nH]cc(C(=O)Cc2cccc(OC)c2)c1C

Procedure:
4-[2-(3-Methoxy-phenyl)-acetyl]-3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (91) was synthesized from 3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (84) and (3-methoxyphenyl)-acetyl chloride following the procedure described in Example 32. crude yield: 95%. 1H-NMR (400 MHz, CDCl3): δ 1.36 (t, 3H), 2.61 (s, 3H), 3.77 (s, 3H), 3.99 (s, 2H), 4.32 (q, 2H), 6.81 (m, 3H), 7.24 (m, 1H), 7.45 (d, 1H), 9.41 (s broad, 1H) ppm. 13C-NMR (100 MHz, CDCl3): δ □□ 11.75, 14.40, 47.59, 55.19, 60.66, 112.19, 115.04, 121.71, 127.22, 129.58, 136.75, 159.75, 193.65 ppm. DEPT (100 MHz, CDCl3): CH3 carbons: 11.75, 14.40, 55.19; CH2 carbons: 47.59, 60.66; CH carbons: 112.19, 115.04, 121.71, 127.22, 129.58 ppm. LC/MS: 60.20%, m/z=301
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([C@@H:13]2[C:18]([C:19]#[N:20])=[C:17]([CH3:21])[N:16]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:15](=[O:32])[N:14]2[CH3:33])=[C:7]([S:9](Cl)(=[O:11])=[O:10])[CH:8]=1)#[N:2].[NH:34]([CH2:38][CH2:39][OH:40])[CH2:35][CH2:36][OH:37].C(N(CC)CC)C>C1COCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C@@H:13]2[C:18]([C:19]#[N:20])=[C:17]([CH3:21])[N:16]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:15](=[O:32])[N:14]2[CH3:33])=[C:7]([S:9]([N:34]([CH2:38][CH2:39][OH:40])[CH2:35][CH2:36][OH:37])(=[O:11])=[O:10])[CH:8]=1)#[N:2]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(=O)(=O)Cl)N(C)C(=O)N1c1cccc(C(F)(F)F)c1
Reactant: OCCNCCO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(=O)(=O)N(CCO)CCO)N(C)C(=O)N1c1cccc(C(F)(F)F)c1
Reaction time: 8 h

Procedure:
Under an atmosphere of argon protective gas, 5-cyano-2-{(4S)-5-cyano-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidin-4-yl}benzenesulfonyl chloride (50 mg, 101 μmol) was dissolved in absolute THF (2.5 ml), diethanolamine (29 μl, 303 μmol; 3 eq.) and triethylamine (10.2 mg, 101 μmol; 1 eq.) were added at room temperature and the mixture was stirred overnight. The reaction mixture was then concentrated under reduced pressure and the residue was purified by preparative HPLC (column: Gromsil C-18, 10 μm; mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10). This gave a colorless amorphous solid (4.9 mg, 9% of theory).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][O:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S(N[C@H](C(O)=O)CCC(O)=O)(=O)=O)=CC=1>CO>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][O:15][S:16]([C:19]2[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2CN(Cc3ccccc3)CCO2)cc1
Agent: Cc1ccc(S(=O)(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1
Solvent: CO
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2CN(Cc3ccccc3)CCO2)cc1
Yield: 77.3 %

Procedure:
To a solution of 4-benzyl-2-(toluene-p-sulphonyloxymethyl)morpholine (18.1 g.) in methanol (100 ml.) was added a solution of (+)-toluene-p-sulphonylglutamic acid (16.0 g.) in methanol (50 ml.) and the mixture was allowed to crystallise during 12 hours. The mixture was filtered, the filtrate was put on one side, and the filtered solids (18.3 g.) were recrystallised from methanol (150 ml.) to obtain the (+)-toluene-p-sulphonylglutamic acid salt of (2S)-4-benzyl-2-(toluene-p-sulphonyloxymethyl)morpholine (14.0 g.), m.p. 184° C. This salt was stirred with a mixture of 2N sodium hydroxide and ether. The ether layer was separated, dried and the ether was distilled to leave optically pure (2S)-4-benzyl-2-(toluene-p-sulphonyloxymethyl)morpholine as an oil, from which was prepared the hydrochloride m.p. 150° C., [α]D25 + 19.4°(c, 5 in methanol).
Reaction SMILES: C[Si](C)(C)CCOC[N:7](COCC[Si](C)(C)C)[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]4[C:25]([CH:26]=3)=[CH:24][CH:23]=[CH:22][CH:21]=4)=[C:12]2[N:11]=[C:10]([CH:27]2[CH2:32][CH2:31][CH:30]([CH2:33][C:34](O)=[O:35])[CH2:29][CH2:28]2)[C:9]=1[Br:37].[CH3:48][S:49]([NH2:52])(=[O:51])=[O:50].Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.ClCCl>[NH2:7][C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]4[C:25]([CH:26]=3)=[CH:24][CH:23]=[CH:22][CH:21]=4)=[C:12]2[N:11]=[C:10]([CH:27]2[CH2:32][CH2:31][CH:30]([CH2:33][C:34]([NH:52][S:49]([CH3:48])(=[O:51])=[O:50])=[O:35])[CH2:29][CH2:28]2)[C:9]=1[Br:37]
Reactant: CS(N)(=O)=O
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1c(Br)c(C2CCC(CC(=O)O)CC2)nc2c(-c3cnc4ccccc4c3)cnn12
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CS(=O)(=O)NC(=O)CC1CCC(c2nc3c(-c4cnc5ccccc5c4)cnn3c(N)c2Br)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 2-(4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-bromo-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexyl)acetic acid (60 mg, 0.081 mmol), methanesulfonamide (12 mg, 0.122 mmol), 4-dimethylaminopyridine (20 mg, 0.163 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (32 mg, 0.163 mmol) in dichloromethane (2.0 ml) was stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuo. The crude mixture was dissolved in methanol (2 ml) and treated with 1N hydrochloride solution (2 ml) at 65° C. for 2 h. The reaction solution was concentrated and purified by prep-LC to afford the title compound (two isomers, cis and trans). Isomer 1: LC/MS RT=3.63 min. Mass calculated for, M+H 557.09, observed 557.09. Isomer 2: LC/MS RT=3.88 min. Mass calculated for, M+H 557.09, observed 557.09.
Reaction SMILES: [C:1]([O:20][C@@H:21]1[C@@H:25]([CH2:26][O:27][C:28]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:24][C@@H:23]([N:47]2[C:56]3[N:55]=[CH:54][N:53]([CH2:57][C:58]4[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=4)[C:51](=[O:52])[C:50]=3[N:49]=[CH:48]2)[C@@H:22]1[OH:64])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[S:72](Cl)([C:75]([F:78])([F:77])[F:76])(=[O:74])=[O:73]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:1]([O:20][C@@H:21]1[C@@H:25]([CH2:26][O:27][C:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:24][C@@H:23]([N:47]2[C:56]3[N:55]=[CH:54][N:53]([CH2:57][C:58]4[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=4)[C:51](=[O:52])[C:50]=3[N:49]=[CH:48]2)[C@@H:22]1[O:64][S:72]([C:75]([F:78])([F:77])[F:76])(=[O:74])=[O:73])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=c1c2ncn([C@@H]3O[C@H](COC(c4ccccc4)(c4ccccc4)c4ccccc4)[C@@H](OC(c4ccccc4)(c4ccccc4)c4ccccc4)[C@H]3O)c2ncn1Cc1ccccc1
Reactant: O=S(=O)(Cl)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=c1c2ncn([C@@H]3O[C@H](COC(c4ccccc4)(c4ccccc4)c4ccccc4)[C@@H](OC(c4ccccc4)(c4ccccc4)c4ccccc4)[C@H]3OS(=O)(=O)C(F)(F)F)c2ncn1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.8 %

Procedure:
To a solution of 3',5'-di-O-trityl-1-benzylinosine (2.0 g, 2.4 mmol), 4-dimethylaminopyridine (290 mg, 2.4 mmol) and triethylamine (480 mg, 4.8 mmol) in methylene chloride (40 mL) is added triflyl chloride (800 mg, 4.8 mmol), and the mixture is stirred at room temperature for 1 hour, and then concentrated in vacuo. The residue is chromatographed on a silica gel column using a mixture of tetrachloromethane and ethyl acetate (5:1 v/v) as the eluent to give 3',5'-di-O-trityl-2'-O-triflyl-1-benzylinosine as a foam (1.82 g, 78% yield), 1H NMR (Me2SO-d6) δ 2.92-2.96 (2H, m, H-5',5"), 3.62-3.69 (1H, m, H-4'), 4.41-4.43 (1H, m, H-3'), 5.23 (2H, s, CH2Ph), 5.89-5.95 (1H, m, H-2'), 6.66 (1 H, d, H-1', J1',2' =6.3 Hz), 7.18-7.34 (35H, m, 2 x Tr and CH2Ph), 8.29, 8.32 (1H each, s, H-2, H-8). Analyses calculated for C56H45F3N4O5S: C, 68.98, H, 4.65, N, 5.63. Found: C, 68.94, H, 4.76, N, 5.63.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)[CH:2]=1.[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[N:24]=[C:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[S:26][CH:27]=1.C(N(C(C)C)CC)(C)C>O>[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[N:24]=[C:25]([N:28]2[CH2:29][CH2:30][N:31]([C:8]([NH:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[O:15])[CH2:32][CH2:33]2)[S:26][CH:27]=1
Reactant: O=C(Nc1cccnc1)OCC(Cl)(Cl)Cl
Reactant: Fc1ccccc1-c1csc(N2CCNCC2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(Nc1cccnc1)N1CCN(c2nc(-c3ccccc3F)cs2)CC1
Temperature: 70 °C
Reaction time: 12 h
Yield: 31.2 %

Procedure:
A mixture of 2,2,2-trichloroethyl pyridin-3-ylcarbamate (225 mg, 0.835 mmol), 1-[4-(2-fluorophenyl)-1,3-thiazol-2-yl]piperazine (200 mg, 0.760 mmol) and diisopropylethylamine (0.265 ml, 1.52 mmol) in dimethylsufoxide (2.5 ml) was stirred at 70° C. for 12 hours. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulafate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of hexane and ethyl acetate to give the desired product (90.9 mg, 31.2%) as a solid.
Reaction SMILES: Cl.[CH:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([S:12](Cl)(=[O:14])=[O:13])[C:6]=2[CH:5]=[CH:4][N:3]=1.[C:16]([O:20][C:21]([NH:23][CH2:24][C:25]([CH3:29])([CH3:28])[CH2:26][NH2:27])=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21]([NH:23][CH2:24][C:25]([CH3:29])([CH3:28])[CH2:26][NH:27][S:12]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[CH:5]=[CH:4][N:3]=[CH:2]2)(=[O:14])=[O:13])=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(CN)CNC(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1cccc2cnccc12
Agent: Cl
Product: CC(C)(CNC(=O)OC(C)(C)C)CNS(=O)(=O)c1cccc2cnccc12
Yield: 97.8 %

Procedure:
According to Reference Example 5, Step B, a reaction was performed by using isoquinoline-5-sulfonyl chloride hydrochloride (7.8 g) and Intermediate 56 (5.97 g) to obtain the title compound (11.36 g).
Reaction SMILES: C(O[C:10]([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][N:14]=1)([CH3:12])[CH3:11])(=O)C1C=CC=CC=1.[H][H]>C(O)C.[C].[Pd]>[CH:10]([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][N:14]=1)([CH3:12])[CH3:11]
Reactant: CC(C)(OC(=O)c1ccccc1)c1nccc2ccccc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)c1nccc2ccccc12
Reaction time: 24 h
Yield: 68.1 %

Procedure:
(a-2-2) Ten grams of 1-(1-benzoyloxy-1-methylethyl)-isoquinoline was dissolved in 100 ml of ethanol, and 2 g of 10% palladium-carbon was dissolved. The mixture was stirred in a stream of hydrogen at room temperature and atmospheric pressure for 24 hours. The reaction mixture was filtered through Celite, and the solvent was distilled off. Distillation under reduced pressure afforded 4.0 g of 1-isopropylisoquinoline. (b) A mixture of 9.4 g of 1-isopropylisoquinoline and 12 g of N-hydroxymethyl dichloroacetamide was dissolved in 94 g of conc. sulfuric acid and 9.5 g of 20% fuming sulfuric acid, and the solution was heated for 3 hours. The reaction mixture was poured into water, made weakly alkaline with an aqueous solution of sodium hydroxide, and extracted with ethyl acetate. The solvent was distilled off, and the residue was recrystallized from ethyl acetate-benzene to afford 20 g of 1-isopropyl-5-dichloroacetylaminomethylisoquinoline having a melting point of 150.7° to 151.0° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([Cl:9])[N:5]=[CH:4][N:3]=1.CO[C:12](OC)(OC)[CH2:13][CH2:14][CH3:15].C1(C)C=CC(S(O)(=O)=O)=CC=1>COCCO>[Cl:9][C:6]1[N:5]=[CH:4][N:3]=[C:2]2[C:7]=1[NH:8][C:12]([CH2:13][CH2:14][CH3:15])=[N:1]2
Reactant: Nc1ncnc(Cl)c1N
Reactant: CCCC(OC)(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COCCO
Product: CCCc1nc2ncnc(Cl)c2[nH]1

Procedure:
To a solution of 4,5-diamino-6-chloropyrimidine (0.289 g, 2 mmol) in 2-methoxyethanol (10 ml) were added trimethylorthobutyrate (0.5 ml, 3 mmol) and p-toluenesulfonic acid (0.03 g), and the mixture was refluxed for 18 hours and then concentrated in vacuo. The residue was partitioned between water and and ethylacetate. The organic phase was then washed with brine and dried (MgSO4). The crude product obtained after evaporation of the solvent was purified by flash column chromatography on silica-gel using ethylacetate/hexane (1:1). The fractions containing pure product were pooled and concentrated in vacuo, and then allowed to stand at room temperature overnight. The crystalline product was filtered and dried. Yield 0.17 g (43%); NMR (CDCl3): δ 1.05 (t, J=9 Hz, 3H), 2.0 (q, 2H), 3.1 (q, 2H), 8.74 (s, 1H); FAB mass-spectra: m/e 197 and 199 (M+H).
Reaction SMILES: [NH2:1]N.[CH3:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH:5]1[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]C1C=CC=C2C(NC(=O)C=12)=O>CO>[CH3:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH:5]1[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH2:1]
Reactant: CN1CCNCC1CCCCCCCCc1cccc2c1C(=O)NC2=O
Reactant: NN
Solvent: CO
Product: CN1CCNCC1CCCCCCCCN

Procedure:
Hydrazine (aqueous solution at 35% by wt.) (0.15 ml; 1.6 mmoles) was added to 8-(N-methylpiperazinyl)octylphthalimide (285 mg; 0.8 mmoles) in methanol (5 ml) and the resulting solution was refluxed. Reaction times and process as per Example 1.