Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:18]3[CH:17]=[CH:16][C:15]([CH3:19])=[C:14]([NH2:20])[C:13]=3[CH:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1.[CH:21]1([NH:24][C:25]2[C:26]3[S:33][CH:32]=[C:31]([C:34](O)=[O:35])[C:27]=3[N:28]=[CH:29][N:30]=2)[CH2:23][CH2:22]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:18]3[C:13](=[C:14]([NH:20][C:34]([C:31]4[C:27]5[N:28]=[CH:29][N:30]=[C:25]([NH:24][CH:21]6[CH2:22][CH2:23]6)[C:26]=5[S:33][CH:32]=4)=[O:35])[C:15]([CH3:19])=[CH:16][CH:17]=3)[CH:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1csc2c(NC3CC3)ncnc12
Reactant: Cc1ccc2c(Nc3ccc(Cl)cc3)nccc2c1N
Product: Cc1ccc2c(Nc3ccc(Cl)cc3)nccc2c1NC(=O)c1csc2c(NC3CC3)ncnc12
Yield: 38.5 %

Procedure:
The procedures of <Step 3> of Example 1 were repeated, except for using N1-(4-chlorophenyl)-6-methylisoquinolin-1,5-diamine (0.04 g, 0.14 mmol) and 4-cyclopropylamino-thieno[3,2-d]pyrimidine-7-carboxylic acid (see WO 2011009687, 0.18 mmol) obtained in <Step 2> of Example 1 to obtain the title compound (27 mg, 38%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([OH:7])=O.C1C=C[C:18]2N(O)N=[N:21][C:19]=2[CH:20]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CC(N)C.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([NH:21][CH:19]([CH3:20])[CH3:18])=[O:7]
Reactant: Nc1cc(C(=O)O)cc(C(F)(F)F)c1
Reactant: On1nnc2ccccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)N
Product: CC(C)NC(=O)c1cc(N)cc(C(F)(F)F)c1
Reaction time: 8 h

Procedure:
To a solution of 3-amino-5-(trifluoromethyl)benzoic acid (0.25 g, 1.22 mmol) in DMF (3 mL) is added HOBt (0.494 g, 3.66 mmol) followed by HATU (0.695 g, 1.83 mmol), propan-2-amine (0.311 mL, 3.66 mmol) and DIEA (0.96 mL, 5.48 mmol). After stirring at it overnight the solution is concentrated and the residue is dissolved in EtOAc, washed with sat aq NaHCO3, brine, and dried over Na2SO4. Following concentration the residue is carried on to next step without further purification. MS (ESI) m/z 247.1 (M+1).
Reaction SMILES: [H-].[Na+].Cl.[NH2:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]1=[O:15].[H][H].I[CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>C1COCC1>[C:23]([O:22][C:20]([CH2:19][N:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:14][CH:5]([NH2:4])[C:6]1=[O:15])=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: [H][H]
Reactant: NC1Cc2ccccc2NC1=O
Reactant: CC(C)(C)OC(=O)CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CN1C(=O)C(N)Cc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
To a suspension of 2.42 gm NaH (50% oil dispersion washed 3×hexanes) in 50 ml of THF at 0° C. was added solid 5 gm (0.025 mol) of 3-aminodihydrocarbostyrilhydrochloride (T. J. McCord, Arch. of Biochem. & Biophys. 102 48 (1963)) stirring at 0° C. until the evolution of hydrogen had ceased at which time the reaction mixture was warmed to room temperature and stirred a further 1 hour. To the stirred reaction mixture was added dropwise a solution of 6 gm of t-butyl iodoacetate in 20 ml of THF stirring a further 2 hours at room temperature at which time the reaction was quenched with 20 ml of saturated NaHCO3. The reaction mixture was diluted with 20 ml of H2O and extracted 2×50 ml of 9:1 ethylacetate:acetonitrile. The organic layers were combined, filtered through MgSO4 and concentrated in vacuo to give 5 gm of 1-t-butoxycarbonylmethyl-3 -aminodihydrocarbostyril.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1)[N:6]=[CH:5]2.[CH:18]1([C:21]([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[CH:37]=[CH:36][C:32]([C:33]([O-])=[O:34])=[CH:31][CH:30]=3)[CH2:25][CH2:24]2)=[O:22])[CH2:20][CH2:19]1>>[CH:18]1([C:21]([NH:17][C:14]2[CH:15]=[CH:16][C:11]([N:7]3[C:8]4[C:4](=[CH:3][C:2]([NH:1][C:33](=[O:34])[C:32]5[CH:36]=[CH:37][C:29]([N:26]6[CH2:27][CH2:28][N:23]([C:21]([CH:18]7[CH2:19][CH2:20]7)=[O:22])[CH2:24][CH2:25]6)=[CH:30][CH:31]=5)=[CH:10][CH:9]=4)[CH:5]=[N:6]3)=[CH:12][CH:13]=2)=[O:22])[CH2:20][CH2:19]1
Reactant: Nc1ccc(-n2ncc3cc(N)ccc32)cc1
Reactant: O=C([O-])c1ccc(N2CCN(C(=O)C3CC3)CC2)cc1
Product: O=C(Nc1ccc2c(cnn2-c2ccc(NC(=O)C3CC3)cc2)c1)c1ccc(N2CCN(C(=O)C3CC3)CC2)cc1

Procedure:
Compound 488 was prepared according to the procedure described in Scheme IV from 5-amino-1-(4-aminophenyl)indazole and 4-(4-cyclopropanecarbonylpiperazino)benzoate. [M+H]+ calcd for C32H32N6O3: 549.25; found: 549.16.
Reaction SMILES: CN(C)[CH:3]=[C:4]([C:10](=O)[C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[N+]([O-])(O)=O.[N+]([O-])(O)=O.[CH3:31][O:32][C:33]1[CH:34]=[C:35]([NH:45][C:46]([NH2:48])=[NH:47])[CH:36]=[CH:37][C:38]=1[N:39]1[CH:43]=[C:42]([CH3:44])[N:41]=[CH:40]1>>[CH3:31][O:32][C:33]1[CH:34]=[C:35]([NH:45][C:46]2[N:48]=[C:10]([C:11]3[CH:12]=[CH:13][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:15][CH:16]=3)[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:3][N:47]=2)[CH:36]=[CH:37][C:38]=1[N:39]1[CH:43]=[C:42]([CH3:44])[N:41]=[CH:40]1
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1ccc(C(F)(F)F)cc1
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Solvent: O=[N+]([O-])O
Product: CCOC(=O)c1cnc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)nc1-c1ccc(C(F)(F)F)cc1

Procedure:
The title compound was prepared from ethyl 3-dimethylamino-2-(4-trifluoromethyl-benzoyl)-acrylate (151 mg, 0.48 mmol) and N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-guanidine dinitrate (133 mg, 0.36 mmol) using in analogous manner the procedure described in example 28b). Obtained as a pale-yellow solid (14 mg, 6%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:12]3[NH:13][C:14]([C:16]([O:18]C)=[O:17])=[CH:15][C:11]=3[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Li+].CO>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:12]3[NH:13][C:14]([C:16]([OH:18])=[O:17])=[CH:15][C:11]=3[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc2c([nH]1)C(c1cccc(Br)c1)CC2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cc2c([nH]1)C(c1cccc(Br)c1)CC2
Yield: 48 %

Procedure:
The title compound was synthesized from methyl 6-(3-bromophenyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.213 g, 0.67 mmol) and lithium hydroxide (0.281 g, 6.70 mmol in 4 mL water), according to General Procedure 7. A 1:2 mixture of methanol (MeOH) and THF (6 mL) was used. The resulting product was purified reverse phase HPLC, eluting with a gradient of 40-100% MeOH: water (with 0.1% formic acid) to afford a light pink solid: 0.098 g (48% yield). 1H NMR (400 MHz, METHANOL-d4) δ ppm 2.23 (ddt, J=13.14, 8.21, 5.27, 5.27 Hz, 1H), 2.62 (ddd, J=14.31, 8.65, 5.34 Hz, 1H), 2.69-2.78 (m, 1H), 2.87-2.98 (m, 1H), 4.24 (dd, J=8.40, 5.17 Hz, 1H), 6.67 (s, 1H), 7.07 (d, J=7.61 Hz, 1H), 7.18 (t, J=7.81 Hz, 1H), 7.25 (s, 1H), 7.33 (d, J=7.86 Hz, 1H); LCMS (ESI+) 306.0 (M+H); HPLC (UV=96.1%), (ELSD=99.3%).
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([S:12]([NH2:15])(=[O:14])=[O:13])[CH:8]=[CH:7]2.[CH3:16][N:17](C=O)C>[Li+].[Cl-].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>[C:16]([C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([S:12]([NH2:15])(=[O:14])=[O:13])[CH:8]=[CH:7]2)#[N:17]
Reactant: CN(C)C=O
Reactant: NS(=O)(=O)c1ccc2cccc(I)c2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Product: N#Cc1cccc2ccc(S(N)(=O)=O)cc12
Temperature: 125 °C
Yield: 30 %

Procedure:
A solution of 8-iodonaphthalene-2-sulfonamide (Intermediate 7, 100 mg, 0.30 mmol), ZnCN (11 μL, 0.180 mmol) and Pd(PPh3)4 (14 mg, 0.012 mmol) in DMF (1.5 mL) was purged with argon for 5 min. The reaction mixture was then heated to 125° C. in a microwave reactor for 30 min. Additional ZnCN (33 μL, 0.54 mmol) and Pd(PPh3)4 (280 mg, 0.24 mmol) were added, and the reaction mixture was heated at 125° C. for 12 h. The reaction mixture was cooled to room temperature, diluted with 10% aq. LiCl solution and extracted with EtOAc (3×). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (22 mg, 30%). 1H NMR (CD3OD) δ 8.77 (d, J=0.9 Hz, 1H), 8.35 (d, J=8.4 Hz, 1H), 8.25 (d, J=8.8 Hz, 1H), 8.19 (d, J=7.3 Hz, 1H), 8.14 (d, J=1.8 Hz, 1H), 7.85-7.75 (m, 1H); MS(ESI+) m/z 250.1 (M+NH4)+.
Reaction SMILES: [H-].[Na+].[N:3]1[C:11]([NH2:12])=[C:10]2[C:6]([N:7]=[CH:8][NH:9]2)=[N:5][CH:4]=1.[C:13]([O:21][CH2:22][C@@H:23]1[C@@H:29]([CH2:30][O:31][C:32](=[O:39])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:28][CH:27]2[CH:25]([O:26]2)[CH2:24]1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.P([O-])([O-])([O-])=O>CN(C=O)C.CO>[C:32]([O:31][CH2:30][C@@H:29]1[C@@H:23]([CH2:22][O:21][C:13](=[O:20])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:24][C@@H:25]([N:7]2[CH:8]=[N:9][C:10]3[C:6]2=[N:5][CH:4]=[N:3][C:11]=3[NH2:12])[C@H:27]([OH:26])[CH2:28]1)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(OC[C@H]1CC2OC2C[C@@H]1COC(=O)c1ccccc1)c1ccccc1
Reactant: Nc1ncnc2nc[nH]c12
Agent: O=P([O-])([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: Nc1ncnc2c1ncn2[C@@H]1C[C@H](COC(=O)c2ccccc2)[C@@H](COC(=O)c2ccccc2)C[C@H]1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.9 %

Procedure:
In an atmosphere of argon gas, 60% sodium hydride (20 mg, 0.65 mole) was added to a suspension of adenine (202.5 mg, 1.34 mmoles) in anhydrous DMF (10 ml). After stirring the mixture at room temperature for one hour, (3S,4S)-3,4-bis(benzoyloxymethyl)-7-oxabicyclo-[4.1.0]heptane (245 mg, 0.67 mmole) was added and the resulting mixture was heated in an oil bath kept at 140° C. for 3 hours. After adding 0.2M phosphate buffer (pH 7.0) to the reaction mixture and stirring the mixture for a while, the mixture was subjected to extraction with ethyl acetate. After drying the extract solution on anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride:methanol=50:1, v/v) to obtain 9-[(1R,2R,4S,5S)-4,5-bis(benzoyloxymethyl)-2-hydroxycyclohexyl]-adenine (161 mg, Yield 48%).
Reaction SMILES: [CH3:1][O:2][C:3]([C@:5]1([CH3:18])[CH2:9][C@H:8]([NH2:10])[CH2:7][N:6]1[CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:4].[OH:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][C:21]=1[C:30](O)=[O:31]>>[CH3:1][O:2][C:3]([C@:5]1([CH3:18])[CH2:9][C@H:8]([NH:10][C:30]([C:21]2[CH:22]=[CH:23][C:24]3[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:20]=2[OH:19])=[O:31])[CH2:7][N:6]1[CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:4]
Reactant: O=C(O)c1ccc2ccccc2c1O
Reactant: COC(=O)[C@]1(C)C[C@H](N)CN1CC1CCCCC1
Product: COC(=O)[C@]1(C)C[C@H](NC(=O)c2ccc3ccccc3c2O)CN1CC1CCCCC1

Procedure:
(2S,4S)-1-Cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-2-methyl-pyrrolidine-2-carboxylic acid methyl ester was prepared from (2S,4S)-4-amino-1-cyclohexylmethyl-2-methyl-pyrrolidine-2-carboxylic acid methyl ester and 1-hydroxy-naphthalene-2-carboxylic acid in an analogous manner to example 1. MS calcd. for C25H33N2O4 [(M+H)+] 425, obsd. 425.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[CH2:12](O)[CH2:13][OH:14].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)(=O)C>C1(C)C=CC=CC=1>[O:11]1[CH2:12][CH2:13][O:14][CH:10]1[C:7]1[CH:8]=[CH:9][C:2]([F:1])=[C:3]([CH:6]=1)[C:4]#[N:5]
Reactant: OCCO
Reactant: N#Cc1cc(C=O)ccc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: N#Cc1cc(C2OCCO2)ccc1F
Temperature: 70 °C

Procedure:
To a solution of 2-fluoro-5-formylbenzonitrile (450 mg, 3 mmol) in toluene (10 mL) was added ethylene glycol (2 mL) and p-toluene sulfonic acid (25 mg). The solution was heated to 70° C. overnight. The solution was cooled to room temperature. Ethyl acetate (100 mL) was added and the solution was washed with sat. sodium bicarbonated (10 mL), water (10 mL) and brine (10 mL), dried over MgSO4 and concentrated to a clear oil (567 mg, 98%). 1H NMR (400 MHz, CDCl3) δ 7.78 (dd 1H, J=6.3, 2.3 Hz), 7.74-7.70 (m, 1H), 7.27-7.24 (m, 1H), 5.80 (s, 1H), 4.14-4.08 (m, 4H).
Reaction SMILES: COC([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]3([CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:23])[CH2:18][CH2:17]3)[N:13]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:12]2)=[CH:7][CH:6]=1)=O.[OH-:38].[Li+].[CH3:40][OH:41]>O>[CH2:25]([O:24][C:22]([N:19]1[CH2:18][CH2:17][C:14]2([N:13]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH2:12][N:11]([C:8]3[CH:7]=[CH:6][CH:5]=[CH:10][C:9]=3[C:40]([OH:41])=[O:38])[C:15]2=[O:16])[CH2:21][CH2:20]1)=[O:23])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: COC(=O)c1ccc(N2CN(c3ccccc3)C3(CCN(C(=O)OCc4ccccc4)CC3)C2=O)cc1
Reactant: CO
Reactant: [OH-]
Agent: [Li+]
Solvent: O
Product: O=C(O)c1ccccc1N1CN(c2ccccc2)C2(CCN(C(=O)OCc3ccccc3)CC2)C1=O

Procedure:
Benzyl 3-(4-(methoxycarbonyl)phenyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (1.16 g, 2.32 mmol) and lithium hydroxide (0.15 g, 3.48 mmol) in methanol (10 mL) and water (1 mL) were stirred at 45° C. for 20 h. The reaction was partially evaporated under vacuum, the residue acidified with 6M hydrochloric acid, and extracted with ethyl acetate. The extract was washed with brine, dried (MgSO4), and evaporated to give product as a white solid (1.13 g, quant.); 1H NMR (DMSO-d6); δ1.89 (d, J=14 Hz, 2H); 2.27-2.33 (m, 2H); 3.56 (m, 2H); 3.98-4.01 (m, 2H); 5.14 (d, 13.6 Hz, 2H); 5.23 (s, 2H); 6.91 (t, J=7.6 Hz, 1H); 6.96 (d, J=8 Hz, 2H); 7.27 (dd, J=7.6 Hz and 8.8 Hz, 2H); 7.32-7.38 (m, 5H); 7.96-8.02 (m, 4H); 12.9 (br s, 1H); MS for C28H27N3O5 m/z 486 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][N:5]([CH:17]([CH2:22]O)[C:18]([O:20][CH3:21])=[O:19])[S:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)(=[O:8])=[O:7].[CH3:28][S:29](Cl)(=[O:31])=[O:30].O>N1C=CC=CC=1>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([S:6]([N:5]([CH2:4][C:3]2[CH:24]=[CH:25][CH:26]=[CH:27][C:2]=2[NH:1][S:29]([CH3:28])(=[O:31])=[O:30])[C:17](=[CH2:22])[C:18]([O:20][CH3:21])=[O:19])(=[O:8])=[O:7])=[CH:10][CH:11]=1
Reactant: COC(=O)C(CO)N(Cc1ccccc1N)S(=O)(=O)c1ccc(OC)cc1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: C=C(C(=O)OC)N(Cc1ccccc1NS(C)(=O)=O)S(=O)(=O)c1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 48 h
Yield: 78 %

Procedure:
To a solution of 1.0 g (2.54 mmol) of methyl [(2-aminobenzyl)-(4-methoxybenzenesulfonyl)amino]-3-hydroxypropionate in 10 ml of pyridine cooled to -5° C. was added 0.432 ml (5.58 mmol) of methanesulfonyl chloride. The mixture was stirred at 0° C. for 48 hours. To the mixture was added ice and H2O and the mixture was extracted with ethyl acetate. The extract was washed with H2O, 2 N citric acid, brine and dried with Na2SO4. The solvent was removed under vacuum and the residue triturated with ethyl acetate-hexane to give 0.90 g of a solid, 128-142° C. Anal. for C19H22N2O7S2 : Calc'd: C,50.2; H,4.9; N,6.2; S,14.1; Found: C,49.6; H,5.0; N,6.9; S,14.0; Mass spectrum (ES) 455.5 (M+H).
Reaction SMILES: C1(C)C=CC=CC=1.[CH2:8]([C@@H:15]1[CH2:19][O:18][C:17](=[O:20])[N:16]1[C:21](=[O:30])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CCN(C(C)C)C(C)C.CO[CH:42]1[N:46]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[C:45]([CH3:55])([CH3:54])[CH2:44][CH2:43]1>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[CH2:8]([C@@H:15]1[CH2:19][O:18][C:17](=[O:20])[N:16]1[C:21](=[O:30])[C@@H:22]([C@H:42]1[N:46]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[C:45]([CH3:55])([CH3:54])[CH2:44][CH2:43]1)[C:23]1[CH:24]=[CH:25][C:26]([Br:29])=[CH:27][CH:28]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Cc1ccc(Br)cc1)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: COC1CCC(C)(C)N1C(=O)OC(C)(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1[C@H]([C@H](C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)c2ccc(Br)cc2)CCC1(C)C
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 85.1 %

Procedure:
TiCl4 in toluene (3.52 mL, 3.52 mmol) was added to a solution of (R)-4-benzyl-3-(2-(4-bromophenyl)acetyl)oxazolidin-2-one (1.26 g, 3.35 mmol) in DCM (30 mL) at −78° C. DIEA (0.64 mL, 3.69 mmol) was then added to the cold stirring solution. The reaction was stirred at −78° C. for 15 minutes, followed by the addition of a solution of tert-butyl 5-methoxy-2,2-dimethylpyrrolidine-1-carboxylate (1.00 g, 4.36 mmol, see Example F) in DCM (10 mL). The reaction was then warmed to −10° C. and stirred for 2 hours. The reaction was quenched with a saturated NH4Cl solution (20 mL), and the organic fraction was isolated, dried over sodium sulfate, filtered and concentrated. The resulting residue was purified by column chromatography to give (S)-tert-butyl 5-((R)-2-((R)-4-benzyl-2-oxooxazolidin-3-yl)-1-(4-bromophenyl)-2-oxoethyl)-2,2-dimethylpyrrolidine-1-carboxylate (1.63 g, 85%) as a solid.
Reaction SMILES: ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]([C:49]2[CH:54]=[CH:53][C:52]([Cl:55])=[CH:51][CH:50]=2)[N:31]2[CH2:34][CH:33]([CH2:35][S:36]([NH:39][C:40]3[CH:41]=[C:42]([CH:46]=[CH:47][CH:48]=3)[C:43]([OH:45])=O)(=[O:38])=[O:37])[CH2:32]2)=[CH:26][CH:25]=1.Cl.[NH2:57][CH2:58][C:59]([N:61]1[CH2:66][CH2:65][O:64][CH2:63][CH2:62]1)=[O:60]>O1CCCC1.ClCCl.C(N(CC)CC)C>[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([CH:30]([C:49]2[CH:54]=[CH:53][C:52]([Cl:55])=[CH:51][CH:50]=2)[N:31]2[CH2:34][CH:33]([CH2:35][S:36]([NH:39][C:40]3[CH:41]=[C:42]([CH:46]=[CH:47][CH:48]=3)[C:43]([NH:57][CH2:58][C:59]([N:61]3[CH2:66][CH2:65][O:64][CH2:63][CH2:62]3)=[O:60])=[O:45])(=[O:37])=[O:38])[CH2:32]2)=[CH:28][CH:29]=1
Reactant: O=C(O)c1cccc(NS(=O)(=O)CC2CN(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)C2)c1
Reactant: NCC(=O)N1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(NCC(=O)N1CCOCC1)c1cccc(NS(=O)(=O)CC2CN(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)C2)c1
Temperature: 20 °C
Reaction time: 8 h

Procedure:
67 mg of 1-hydroxybenzotriazole, 0.14 cm3 of triethylamine and 270 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride are added successively to a solution of 500 mg of 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}methanesulphonylamino)benzoic acid and 215 mg of 2-amino-1-morpholin-4-ylethanone hydrochloride in 15 cm3 of tetrahydrofuran. The reaction mixture is left stirring overnight at a temperature in the region of 20° C. After concentration of the reaction medium to dryness under reduced pressure, the residue obtained is taken up with dichloromethane. The organic phase is washed with water, dried, and concentrated to dryness under reduced pressure, to give a reaction crude which is purified by flash chromatography on a Merck 30 g silica cartridge (elution gradient: 100/0 to 95/5 dichloromethane/methanol). After concentration of the fractions under reduced pressure, a white foam is obtained which crystallizes after trituration with diethyl ether. After filtration and drying using a vane pump, 470 mg of 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}methanesulphonylamino)-N-(2-morpholin-4-yl-2-oxoethyl)benzamide are thus obtained in the form of white crystals.
Reaction SMILES: CS(C)=O.[CH2:5]([O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:28]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:22]3[N:23]=[CH:24][N:25]=[C:26](Cl)[C:21]=3[CH:20]=2)=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[H-].[Na+].[NH2:39][C:40]1[CH:45]=[CH:44][C:43]([OH:46])=[CH:42][C:41]=1[Cl:47]>O>[CH2:5]([O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[N:28]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:35])([CH3:36])[CH3:34])[C:22]3[N:23]=[CH:24][N:25]=[C:26]([O:46][C:43]4[CH:44]=[CH:45][C:40]([NH2:39])=[C:41]([Cl:47])[CH:42]=4)[C:21]=3[CH:20]=2)=[CH:17][CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C[Si](C)(C)CCOCn1c(-c2ccc(OCc3ccccc3)cc2)cc2c(Cl)ncnc21
Reactant: Nc1ccc(O)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: C[Si](C)(C)CCOCn1c(-c2ccc(OCc3ccccc3)cc2)cc2c(Oc3ccc(N)c(Cl)c3)ncnc21
Reaction time: 0.17 h

Procedure:
After adding 12 ml of dimethylsulfoxide to the 6-(4-benzyloxyphenyl)-4-chloro-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine synthesized in Production Example 153-4, 141 mg (1.5 equivalents) of sodium hydride (60% dispersion, Aldrich) and 507 mg (1.5 equivalents) of 4-amino-3-chlorophenol were added while stirring, and stirring was then continued at room temperature for 10 minutes and then at 135-140° C. for 4 hours. The mixture was returned to room temperature, water was added, and liquid separation and extraction were performed with an ethyl acetate:tetrahydrofuran (5:1) mixed solvent. The organic layer was dried over sodium sulfate, concentrated and subjected to NH silica gel column chromatography (hexane-ethyl acetate) to obtain 1.20 g of the title compound.
Reaction SMILES: Cl.Cl.[CH2:3]1[C:12]2[C:7](=[CH:8][CH:9]=[N:10][CH:11]=2)[CH2:6][CH2:5][N:4]1[C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1.C(N(CC)C(C)C)(C)C.[F:29][C:30]([F:41])([F:40])[C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=1)[C:34](Cl)=[O:35]>C(Cl)Cl>[CH2:3]1[C:12]2[C:7](=[CH:8][CH:9]=[N:10][CH:11]=2)[CH2:6][CH2:5][N:4]1[C:13]1[CH:19]=[CH:18][C:16]([NH:17][C:34](=[O:35])[C:33]2[CH:37]=[CH:38][CH:39]=[C:31]([C:30]([F:29])([F:40])[F:41])[CH:32]=2)=[CH:15][CH:14]=1
Reactant: Nc1ccc(N2CCc3ccncc3C2)cc1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1ccc(N2CCc3ccncc3C2)cc1)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83.2 %

Procedure:
To a mixture of 4-(3,4-dihydro-2,7-naphthyridin-2(1H)-yl)aniline dihydrochloride (75.0 mg, 0.251 mmol) and N,N-diisopropylethylamine (0.153 mL, 0.88 mmol) in 3.0 mL CH2Cl2 at rt was added 3-(trifluoromethyl)benzoyl chloride (0.041 mL, 0.277 mmol) and the reaction stirred for 15 min at rt. The reaction was evaporated, then partitioned between EtOAc and H2O/brine mixture, the EtOAc layer washed with aqueous Na2CO3 solution, brine, and dried with anhydrous Na2SO4. The EtOAc solution was filtered past a silica gel plug, rinsed with EtOAc, and evaporated to a yellow solid. The solid was recrystallized from EtOAc/hexane to give the title compound as a light tan solid (83 mg, 83%). 1H NMR (DMSO-d6) δ: 10.28 (s, 1H), 8.44 (s, 1H), 8.32 (d, J=5.0 Hz, 1H), 8.23-8.30 (m, 2H), 7.95 (d, J=7.9 Hz, 1H), 7.74-7.80 (m, 1H), 7.61-7.68 (m, 2H), 7.19 (dd, J=5.0, 0.6 Hz, 1H), 7.03-7.09 (m, 2H), 4.40 (s, 2H), 3.54 (t, J=5.9 Hz, 2H), 2.93 (t, J=5.9 Hz, 2H).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([NH2:9])[N:6]=[N:7][CH:8]=1.C(=O)(O)[O-].[Na+].[CH2:17](O)[CH3:18]>O>[F:11][C:2]([F:1])([F:10])[C:3]1[CH:8]=[N:7][N:6]2[CH:17]=[CH:18][N:9]=[C:5]2[CH:4]=1
Reactant: CCO
Reactant: Nc1cc(C(F)(F)F)cnn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: FC(F)(F)c1cnn2ccnc2c1
Temperature: 130 °C

Procedure:
5-(Trifluoromethyl)pyridazin-3-amine (6.79 g, 41.6 mmol) was dissolved in a mixture of ethanol (133 mL) and water (33.3 mL) and 50% aq. solution of chloroacetylaldehyde (26.9 mL, 208 mmol) and sodium bicarbonate (17.5 g, 208 mmol) was added. The reaction was sealed in a pressure vessel and heated to 130° C. for 6 h. The reaction was then cooled to room temperature. Water was added and the mixture filtered through celite. The aqueous layer was extracted with a 3:1 mixture of CHCl3:Isopropanol (×3). The organic layers were collected, dried with magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography to afford the title compound as an orange solid. 1H NMR (500 MHz, CDCl3) δ 8.52 (s, 1H); 8.27 (s, 1H); 8.13 (s, 1H); 7.97 (s, 1H). LRMS (APCI) calc'd for (C7H4F3N3) [M+H]+, 187.1. found 187.1.