Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl[C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH2:16][CH2:17][CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[N:5][CH:4]=1.[Cl:24][C:25]1[C:31]([OH:32])=[CH:30][C:28]([NH2:29])=[C:27]([F:33])[CH:26]=1>CC(O)CCC>[Cl:24][C:25]1[C:31]([OH:32])=[CH:30][C:28]([NH:29][C:3]2[C:12]3[C:7](=[CH:8][C:9]([O:15][CH2:16][CH2:17][CH2:18][N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)=[C:10]([O:13][CH3:14])[CH:11]=3)[N:6]=[N:5][CH:4]=2)=[C:27]([F:33])[CH:26]=1
Reactant: COc1cc2c(Cl)cnnc2cc1OCCCN1CCCC1
Reactant: Nc1cc(O)c(Cl)cc1F
Agent: Cl
Solvent: CCCC(C)O
Product: COc1cc2c(Nc3cc(O)c(Cl)cc3F)cnnc2cc1OCCCN1CCCC1

Procedure:
A solution of 4-chloro-6-methoxy-7-(3-pyrrolidinopropoxy)cinnoline hydrochloride (0.1 g, 0.25 mmol) and 4-chloro-2-fluoro-5-hydroxyaniline (57 mg, 0.35 mmol), (prepared as described in EP 061741 A2), in 2-pentanol (5ml) was heated at 120° C. for 2.5 hours. The solid was filtered off, washed with isopropanol and then ether and dried under vacuum to give 4-(4-chloro-2-fluoro-5-hydroxyanilino)-6-methoxy-7-(3-pyrrolidinopropoxy)cinnoline as the hydrochloride salt (yellow solid, 94 mg, 72%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[O:10])=[C:4]([CH3:17])[CH:3]=1.Cl[C:19]1[N:24]=[C:23]([NH:25][CH3:26])[C:22]([C:27]([F:30])([F:29])[F:28])=[CH:21][N:20]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>O1CCOCC1.C(Cl)Cl>[Cl:8][C:7]1[C:2]([NH:1][C:19]2[N:24]=[C:23]([NH:25][CH3:26])[C:22]([C:27]([F:30])([F:28])[F:29])=[CH:21][N:20]=2)=[CH:3][C:4]([CH3:17])=[C:5]([C:9]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[O:10])[CH:6]=1
Reactant: Cc1cc(N)c(Cl)cc1C(=O)N1CCOCC1
Reactant: CNc1nc(Cl)ncc1C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: CNc1nc(Nc2cc(C)c(C(=O)N3CCOCC3)cc2Cl)ncc1C(F)(F)F
Temperature: 100 °C
Yield: 53.3 %

Procedure:
A mixture of (4-amino-5-chloro-2-methylphenyl)(morpholino)methanone (79 mg, 0.31 mmol), 2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine (66 mg, 0.31 mmol) and para-toluene sulfonic acid (59 mg, 0.31 mmol) in dioxane (4 mL) was heated to 100° C. for 4 h. Saturated aqueous sodium bicarbonate solution (10 mL) and DCM (10 mL) were added and the organic phase was passed through a hydrophobic frit. The solvent was removed in vacuo and the residue was purified by reversed phase HPLC to give (5-chloro-2-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)(morpholino)methanone (71 mg, 53%) as an off-white solid. LCMS (10 cm_ESCI_Bicarb_MeCN): [M+H]+=430 at 3.47 min. 1H NMR (400 MHz, CDCl3): δ 8.55 (s, 1H), 8.21 (d, 1H), 7.57 (s, 1H), 7.22 (s, 1H), 5.30 (br s, 1H), 3.79 (br d, 4H), 3.60 (br s, 2H), 3.32 (br s, 2H), 3.11 (d, 3H), 2.32 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:5]=1[N:11]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:14])=[O:13].[CH2:31](Cl)[O:32][CH2:33][CH2:34][O:35][CH3:36]>>[CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:31][O:32][CH2:33][CH2:34][O:35][CH3:36])[C:5]=1[N:11]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:13])=[O:14]
Reactant: COC(=O)c1cccc(O)c1N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Reactant: COCCOCCl
Product: COCCOCOc1cccc(C(=O)OC)c1N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Yield: 94 %

Procedure:
In the same manner as described in Example 38, 0.40 g (0.937 mmol) of the product of Example 37 and 0.134 mL (1.171 mmol) of MEM-Cl provided 0.454 g (94%) of the desired product as a colorless oil. Electrospray Mass Spec: 516.2 (M+H)+
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH2:7])=[CH:5][C:4]([CH3:8])=[N:3]1.Cl[C:10]([O:12][CH2:13][C:14]([Cl:17])([Cl:16])[Cl:15])=[O:11].O>CC(N(C)C)=O>[CH3:1][N:2]1[C:6]([NH:7][C:10](=[O:11])[O:12][CH2:13][C:14]([Cl:17])([Cl:16])[Cl:15])=[CH:5][C:4]([CH3:8])=[N:3]1
Reactant: Cc1cc(N)n(C)n1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1cc(NC(=O)OCC(Cl)(Cl)Cl)n(C)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 40.8 %

Procedure:
To a solution of 1,3-dimethyl-1H-pyrazol-5-amine (500 mg, 4.50 mmol) in dimethylacetamide (15 ml) was added 2,2,2-trichloroethyl chloroformate (0.747 ml, 5.40 mmol) with ice-cooling, and the mixture was stirred at 0° C. for 1 hour. 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 sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give 526 mg (40.8%) of the desired product as an oil.
Reaction SMILES: [F:1][C:2]1[CH:14]=[C:13]([CH2:15]O)[CH:12]=[C:11]([O:17][CH3:18])[C:3]=1[O:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].P(Br)(Br)[Br:20]>ClCCl>[Br:20][CH2:15][C:13]1[CH:12]=[C:11]([O:17][CH3:18])[C:3]([O:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:2]([F:1])[CH:14]=1
Reactant: BrP(Br)Br
Reactant: CCOC(=O)COc1c(F)cc(CO)cc1OC
Solvent: ClCCl
Product: CCOC(=O)COc1c(F)cc(CBr)cc1OC
Yield: 52.2 %

Procedure:
The compound was prepared according to general procedure G with ethyl 2-(2-fluoro-4-(hydroxymethyl)-6-methoxyphenoxy)acetate (0.4 mmol) in dichloromethane (5 ml) and PBr3 (0.4 mmol). 67 mg of compound were obtained (54% yield). This compound was used without further purification. 1H NMR (250 MHz, CDCl3): δ 1.29 (t, J=7.0 Hz, 3H), 3.89 (s, 3H), 4.25 (q, J=7.0 Hz, 2H), 4.41 (s, 2H), 4.71 (s, 2H) 6.74 (m, 1H), 6.81 (m, 1H). MS (ESI): m/z 319.9 [M+H]+
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:3]=1.[C:29]1([NH2:36])[C:30]([NH2:35])=[CH:31][CH:32]=[CH:33][CH:34]=1.[F:37][C:38]([F:43])([CH3:42])[C:39](O)=O>>[F:37][C:38]([C:42]1[N:36]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[C:7]([CH2:12][N:13]4[CH2:14][CH2:15][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:17][CH2:18]4)[N:8]3[CH3:11])=[C:4]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[N:3]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[N:35]=1)([F:43])[CH3:39]
Reactant: Nc1ccccc1N
Reactant: CC(F)(F)C(=O)O
Reactant: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Product: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(-n3c(C(C)(F)F)nc4ccccc43)nc21

Procedure:
Following the procedures for 157 and General Procedure J, 2-(1-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol (1.21 g, 2.96 mmol) and benzene-1,2-diamine were reacted followed by condensation with 2,2-difluoropropionic acid to give 197. LCMS m/z: 555.3 (MH+)
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][C:15]#[N:16])[CH:9]=1.N1CCCCC1>CO>[N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14](=[CH:6][C:2]2[NH:1][CH:5]=[CH:4][CH:3]=2)[C:15]#[N:16])[CH:9]=1
Reactant: O=Cc1ccc[nH]1
Reactant: N#CCc1cccnc1
Solvent: CO
Solvent: C1CCNCC1
Product: N#CC(=Cc1ccc[nH]1)c1cccnc1
Yield: 47.8 %

Procedure:
A mixture of pyrrole-2-carboxaldehyde (2.85 g; 30 mmol), 3-pyridylacetonitrile (3.54 g; 30 mmol), and piperidine (2 mL) in methanol (50 mL) was refluxed for 18 hours. The dark precipitate formed was separated by filtration. Dark solid was treated with charcoal in hot methanol to obtain 2.8 g (48%) of the title compound as a yellow solid, m.p. 139°-142° C. Anal. Calcd. for C12H9N3 : C, 73.83; H, 4.65; N, 21.52. Found: C, 73.71; H, 4.57; N, 21.76. Mass spectrum: (EI; M+) m/z 195. 1H-NMR (DMSO-d6 ; 200 MHz) δ 11.5 (s, 1H), 8.8 (d, 1H), 8.5 (d, 1H), 7.92-7.96 (m, 1H), 7.8 (s, 1H), 7.43-7.52 (m, 1H), 7.2 (d, 2H), 6.38-6.4 ppm (q, 1H).
Reaction SMILES: [OH:1][C:2]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([OH:24])[CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.[C:25](Cl)(=[O:27])[CH3:26].CCN(CC)CC.C([O-])(O)=O.[Na+]>CC#N>[C:25]([N:8]1[CH2:9][CH2:10][CH2:11][N:5]([CH2:4][CH2:3][C:2]([OH:1])([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([OH:24])[CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6][CH2:7]1)(=[O:27])[CH3:26]
Reactant: Oc1cccc(C(O)(CCN2CCCNCC2)c2ccccc2)c1
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(=O)N1CCCN(CCC(O)(c2ccccc2)c2cccc(O)c2)CC1
Yield: 18 %

Procedure:
Compound No. 296 (16 mg, 18%) was prepared from 1-[3-hydroxy-3-(3-hydroxyphenyl)-3-phenylpropyl]homopiperazine (Compound No. 295, 78 mg, 0.24 mmol) and acetyl chloride (19 mg, 1.0 equiv). Acetyl chloride and Et3N (121 mg, 1.2 mmol, 5.0 equiv) were added to a solution of 1-[3-hydroxy-3-(3-hydroxyphenyl)-3-phenylpropyl]homopiperazine (Compound No. 295) in CH3CN (2.0 mL). The reaction mixture was stirred at room temperature for 30 min. saturated aqueous NaHCO3 (10 mL) was added to the reaction mixture and the mixture was extracted with AcOEt (3×15 mL). The combined extracts were dried over MgSO4. The solvent was removed under reduced pressure to afford an oil which was purified by column chromatography (SiO2, 3-10% CH3OH/CH2Cl2) to give 1-acetyl-4-[3-hydroxy-3-(3-hydroxyphenyl)-3-phenylpropyl]homopiperazine (Compound No. 296): 16 mg, 18% yield, colorless oil: RPLC tR=4.75 min (89%), 220 nm (Method B); ESI/MS m/e 369.3 (M++H, C22H29N2O3).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH:11]([CH3:13])[CH3:12])[C:3]=1[S:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH:22]#[C:23][CH3:24]>C(N(CC)CC)C.C(OCC)C.[Cu]I>[CH:11]([O:10][C:4]1[C:3]([S:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:2]([C:22]#[C:23][CH3:24])[CH:7]=[CH:6][C:5]=1[O:8][CH3:9])([CH3:13])[CH3:12]
Reactant: COc1ccc(I)c(SCc2ccccc2)c1OC(C)C
Reactant: C#CC
Agent: [Cu]I
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC#Cc1ccc(OC)c(OC(C)C)c1SCc1ccccc1
Temperature: -40 °C
Reaction time: 3 h
Yield: 67.3 %

Procedure:
A mixture of the product of Step A (0.123 g; 0.296 mmol), Cl2Pd(PPh3)2 (0.040 g; 0.057 mmol), CuI (0.014 g; 0.073 mmol) in anhydrous triethylamine (3 ml) was cooled to −40° C., degassed under reduced pressure and saturated with dry N2. The propyne gas (0.45 g; 11.2 mmol) was added to it at −40° C. The reaction flask was sealed with septum and allowed to warm up to room temperature and stirred for 3 h at room temperature and diluted to 20 ml with diethyl ether and solid precipitated, filtered off. The filtrate was evaporated to dryness under reduced pressure and the residue, purified by flash column chromatography (SiO2, hexane, hexane/ethyl acetate, 9:1) to give the title compound (0.065 g; 67% yield) as colourless syrup. 1H-NMR (CDCl3) 1.26 (d, 6H, J=6.17 Hz); 2.09 (s, 3H); 3.79 (s, 3H); 4.2 (s, 2H); 4.44 (m, 1H, J=6.17 Hz); 6.73 (d, 1H, J=8.53 Hz); 7.12 (d, 1H, J=8.53 Hz); 7.15-7.4 (m, 5H).
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I:20][CH2:21][I:22]>C1C=CC=CC=1>[I-:20].[I:22][CH2:21][P+:7]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: ICI
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: IC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [I-]
Temperature: 25 °C
Yield: 55.7 %

Procedure:
A solution of triphenylphosphine (6.56 g, 25 mmol) and diiodomethane (8.7 g, 32.5 mmol) in benzene (25 mL) was heated at 60° C. for 20 hours. The mixture was cooled to room temperature and the precipitated salt was collected by filtration, washed with benzene and dried to give the title material (7.38 g, 56%).
Reaction SMILES: C([O:3][C:4](=[O:19])[C:5]1[CH:10]=[C:9]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:8]([CH2:15][CH:16]([CH3:18])[CH3:17])=[N:7][CH:6]=1)C.[ClH:20]>>[ClH:20].[CH2:11]([C:9]1[C:8]([CH2:15][CH:16]([CH3:18])[CH3:17])=[N:7][CH:6]=[C:5]([CH:10]=1)[C:4]([OH:19])=[O:3])[CH:12]([CH3:14])[CH3:13]
Reactant: CCOC(=O)c1cnc(CC(C)C)c(CC(C)C)c1
Agent: Cl
Product: CC(C)Cc1cc(C(=O)O)cnc1CC(C)C
Temperature: 25 °C

Procedure:
A solution of 5,6-diisobutyl-nicotinic acid ethyl ester (52 mg, 0.2 mmol) in 6 N aq. HCl (2 mL) is stirred at 65° C. for 15 h before it is cooled to rt and extracted with diethyl ether (2×10 mL). The aq. phase is evaporated and the residue is dried under HV to give 5,6-diisobutyl-nicotinic acid hydrochloride (0.12 g) as a colourless solid; LC-MS: tR=0.73 min, [M+1]+=236.40.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([N:9]2[CH2:13][CH2:12][C:11]([C:18]3[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[CH:19]=3)([C:14]([F:17])([F:16])[F:15])[CH2:10]2)[CH:6]=[CH:5][C:3]=1[NH2:4].C(OCC)(OCC)OCC.[N-:36]=[N+:37]=[N-:38].[Na+].[C:40](O)(=O)C>O>[Br:1][C:2]1[CH:8]=[C:7]([N:9]2[CH2:13][CH2:12][C:11]([C:18]3[CH:19]=[C:20]([Cl:25])[CH:21]=[C:22]([Cl:24])[CH:23]=3)([C:14]([F:15])([F:16])[F:17])[CH2:10]2)[CH:6]=[CH:5][C:3]=1[N:4]1[CH:40]=[N:38][N:37]=[N:36]1
Reactant: CC(=O)O
Reactant: Nc1ccc(N2CCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Br
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(OCC)OCC
Product: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)CCN(c2ccc(-n3cnnn3)c(Br)c2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.6 %

Procedure:
To the mixture of 2-bromo-4-[3-(3,5-dichlorophenyl)-3-(trifluoromethyl)-pyrrolidin-1-yl]aniline (0.60 g), triethyl orthoformate (0.98 g) and sodium azide (0.38 g) was added acetic acid (1.1 g), and the mixture was then heated with stifling at 100° C. for 4 hours. The mixture was cooled to room temperature and then poured into water, which was then extracted twice with ethyl acetate. The organic layer was combined, which was then washed with water and dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the solvent was distilled away under the reduced pressure, and the residue was then purified by silica gel chromatography to yield 1-{2-bromo-4-[3-(3,5-dichlorophenyl)-3-(trifluoromethyl)-pyrrolidin-1-yl]phenyl}-1H-tetrazole (0.52 g). m.p. 193-194° C.
Reaction SMILES: CC(C[AlH]CC(C)C)C.[O:10]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[O:13][CH2:12][C:11]1=[O:20]>C1(C)C=CC=CC=1>[OH:20][CH:11]1[O:10][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[O:13][CH2:12]1
Reactant: O=C1COc2ccccc2O1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Product: OC1COc2ccccc2O1
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 90.9 %

Procedure:
The mixture is warmed at room temperature, then heated to reflux for 2 hours. The organic phase is washed with water, 5% aqueous sodium hydroxyde and then with water. After drying on Na2SO4, the solvent is evaporated to dryness under vacuum and the crude material is crytallized from cyclohexane-Et2O to give 1,4-benzodioxan-2-one (10 g) m.p. 52°-54° C. A molar solution of DIBAH in toluene (73 ml) is added dropwise to a stirred solution of 1,4-benzodioxan-2-one (8.9 g) in dry toluene (100 ml), cooled at -70° C. during 40 minutes. Stirring at this temperature is continued for 15 minutes, then the excess reagent is destroyed by adding 2N-isopropanol in toluene (75 ml), under stirring, at -70°÷-60° C. The mixture is warmed at room temperature and treated with 30% NaH2PO4 aqueous solution (6 ml) and 25 g of anhydrous Na 2 SO4, for 4 hours, under stirring. The inorganic material is filtered out and the eluate is evaporated to dryness to give 8.2 g of 2-hydroxy-1,4-benzodioxan. A stirred solution of this δ-lactol (7.8 g) in ethanol (30 ml) is treated with a solution of cysteamine hydrochloride (7.36 g) and potassium acetate (6.5 g) in water (12 ml). Stirring is continued for 45 minutes, then a crystalline precipitate of 2-[(o-hydroxyphenoxy)methyl]thiazolidine (8.1 g) is obtained. M.p. 76°-78° C.
Reaction SMILES: [NH2:1][S:2]([CH2:5][CH2:6][CH2:7][C:8]([OH:10])=O)(=[O:4])=[O:3].CCN(C(C)C)C(C)C.CC(C)N=C=NC(C)C.C1C=CC2N(O)N=NC=2C=1.[CH:39]1([C:45]2[C:46]3[CH:47]=[CH:48][C:49]([C:70]([O:72][CH3:73])=[O:71])=[CH:50][C:51]=3[N:52]3[C:59]=2[C:58]2[CH:60]=[CH:61][CH:62]=[CH:63][C:57]=2[O:56][CH2:55][C@H:54]([N:64]([CH3:69])[CH2:65][CH2:66][NH:67][CH3:68])[CH2:53]3)[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1>CN(C=O)C>[NH2:1][S:2]([CH2:5][CH2:6][CH2:7][C:8]([N:67]([CH3:68])[CH2:66][CH2:65][N:64]([CH3:69])[C@@H:54]1[CH2:53][N:52]2[C:51]3[CH:50]=[C:49]([C:70]([O:72][CH3:73])=[O:71])[CH:48]=[CH:47][C:46]=3[C:45]([CH:39]3[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]3)=[C:59]2[C:58]2[CH:60]=[CH:61][CH:62]=[CH:63][C:57]=2[O:56][CH2:55]1)=[O:10])(=[O:4])=[O:3]
Reactant: NS(=O)(=O)CCCC(=O)O
Reactant: CNCCN(C)[C@H]1COc2ccccc2-c2c(C3CCCCC3)c3ccc(C(=O)OC)cc3n2C1
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@@H](N(C)CCN(C)C(=O)CCCS(N)(=O)=O)COc1ccccc1-3
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-(aminosulfonyl)butanoic acid (1.2 eq.), DIPEA (2 eq.), DIC (1.1 eq.) and HOBT (1.1 eq.) were added to a solution of methyl(7R)-14-cyclohexyl-7-{methyl[2-(methylamino)ethyl]amino}-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate (0.07 M) in DMF. The reaction was stirred under N2 at RT overnight. The mixture was then partitioned between sat. aq. NaHCO3 and EtOAc. The combined organics were washed with 1N HCl followed by brine, dried (Na2SO4), filtered and concentrated in vacuo. The product was used in the next step without further purification. (ES+) m/z 625 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=O.Cl.[NH:13]1[CH2:18][CH2:17][CH:16]([C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=2)[CH2:15][CH2:14]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=2)[CH2:15][CH2:14]1)=[O:7]
Reactant: N#Cc1ccc(C2CCNCC2)cc1
Reactant: Cc1ccc(C(=O)O)cc1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)N2CCC(c3ccc(C#N)cc3)CC2)cc1N
Yield: 100.2 %

Procedure:
A solution of 3-amino-4-methylbenzoic acid (1.36 g, 9.0 mmol), (4-(piperidin-4-yl)benzonitrile HCl salt (compound 1.5, 2.0 g, 9.0 mmol), EDCI (1.89 g, 9.9 mmol), HOBT (1.66 g, 9.9 mmol, with 20% H2O) and DIEA (3.13 ml, 18.0 mmol) in DMF (50 ml) was stirred at room temperature overnight. The reaction mixture was poured into cold water (300 ml) and off white solids precipitated. The precipitate was filtered, washed with water and dried under reduced pressure in an oven to yield 2.88 g (100%) of the title compound. m/z (ES+) 320 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]([CH2:29][CH3:30])[C:4](=[O:28])[C:5]1[CH:10]=[CH:9][C:8]([CH:11]([N:20]2[C:24]([CH3:25])=[C:23](I)[C:22]([CH3:27])=[N:21]2)[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)=[CH:7][CH:6]=1)[CH3:2].[C:31]([C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1)(O)=[O:32].C(=O)([O-])[O-].[Na+].[Na+]>CCO>[CH2:1]([N:3]([CH2:29][CH3:30])[C:4](=[O:28])[C:5]1[CH:10]=[CH:9][C:8]([CH:11]([N:20]2[C:24]([CH3:25])=[C:23]([C:37]3[CH:38]=[CH:39][C:34]([CH:31]=[O:32])=[CH:35][CH:36]=3)[C:22]([CH3:27])=[N:21]2)[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCN(CC)C(=O)c1ccc(C(c2cccc(OC)c2)n2nc(C)c(I)c2C)cc1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCN(CC)C(=O)c1ccc(C(c2cccc(OC)c2)n2nc(C)c(-c3ccc(C=O)cc3)c2C)cc1
Temperature: -78 °C
Yield: 92.9 %

Procedure:
To a stirring solution of N,N-Diethyl-4-[(4-iodo-3,5-dimethyl-pyrazol-1-yl)-(3-methoxy-phenyl)-methyl]-benzamide (300 mg, 0.58 mmol) in 40 mL EtOH/H20 (9:1) at room temperature was added 4-carboxybenzeneboronic acid (261 mg, 1.74 mmol), sodium carbonate (184 mg, 1.74 mmol) and tetrakistriphenylphosphine palladium (0) (200 mg, 0.174 mmol). The mixture was cooled to −78° C., de-oxygenated under reduced pressure and purged with nitrogen gas. The mixture was refluxed for 3 h, cooled to room temperature, filtered through a Celite pad and concentrated under reduce pressure. Purification of the crude material was accomplished by flash chromatography on a 2×15 cm column, eluting with 50% ethyl acetate/hexanes, collecting 8 mL fractions. The product containing fractions were collected and concentrated to give the desired product (267 mg, 93%) as a clear colorless solid. 300 MHz 1H NMR (CDCl3) δ 10.1 (s, 1H), 7.90 (d, J=8.3 Hz, 2H), 7.21-7.42 (m, 7H), 6.78-6.86 (m, 3H), 6.57 (s, 1H), 3.75 (s, 3H), 3.52 (brs, 2H), 3.27 (brs, 2H), 2.26 (s, 6H), 1.24 (brs, 3H), 1.22 (brs, 3H); MS (M+1) 496.2.
Reaction SMILES: [ClH:1].[CH:2]1([C:11]([OH:13])=[O:12])[CH:10]2[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][NH:3]1.[C:14](O)(=O)C.[CH3:18]COCC>CO.[Rh]>[ClH:1].[CH:2]1([C:11]([O:13][CH3:14])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][NH:3]1.[ClH:1].[CH:2]1([C:11]([O:13][CH3:18])=[O:12])[CH:10]2[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][NH:3]1
Reactant: CC(=O)O
Reactant: CCOCC
Reactant: O=C(O)C1NCC2CCCCC21
Agent: [Rh]
Agent: Cl
Solvent: CO
Product: COC(=O)C1NCC2CCCCC21
Product: COC(=O)C1NCc2ccccc21

Procedure:
Octahydro-1H-isoindole-1-carboxylic acid hydrochloride used as an intermediate in this preparation is obtained by the following method. Following a procedure given in Gazz. Chim. Ital, 106, 65(1976), 2,3-dihydro-1H-isoindole-1-carboxylic acid, methyl ester, hydrochloride is prepared. This compound, 2.14 g, is dissolved in 100 ml of methanol and 5 ml of acetic acid and hydrogenated over 0.5 g of 10% rhodium/carbon catalyst. The catalyst is removed by filtration and the filtrate is concentrated to give a residue which solidifies on trituration with ether. Recrystallization from methanol-ether gives a pure sample of methyl octahydro-1H-isoindole-1-carboxylate hydrochloride, mp 181°-183° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][C:16]2[S:20][C:19]([Cl:21])=[N:18][C:17]=2[Cl:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.[CH:27](=O)[CH:28]([CH3:30])[CH3:29].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].ClC1SC(CO)=C(Cl)N=1>CC(OC)(C)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:15][C:16]2[S:20][C:19]([Cl:21])=[N:18][C:17]=2[Cl:22])[CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(NCc2sc(Cl)nc2Cl)CC1
Reactant: CC(C)C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: OCc1sc(Cl)nc1Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: COC(C)(C)C
Product: CC(C)CN(Cc1sc(Cl)nc1Cl)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Yield: 78 %

Procedure:
To a solution of 4-{[(2,4-dichloro-thiazol-5-yl)methyl]-amino}-piperidine-1-carboxylic acid t-butyl ester (330 g, 0.9 mol, 1 equiv. mol) in 3.5 L MTBE is added acetic acid (57.2 g, 0.95 mol, 1.06 equiv. mol), isobutyraldehyde (97.3 g, 1.35 mol, 1.5 equiv. mol) and sodium triacetoxy borohydride (305 g, 1.44 mol, 1.6 equiv. mol) suspension in 0.5 L of MTBE. A slight exotherm takes place temperature increases from 24 to 26° C. After 5 h at room temperature the reaction mixture is quenched with 1.3 L water and 30% sodium hydroxide (500 ml). The yellow organic upper phase is washed with 2 L water, then with 2 L of brine. The organic layer is then concentrated under vacuum. The crude product is isolated as yellow powder, 395 g (HPLC 92% area), contaminated by ˜7% of (2,4-dichloro-thiazol-5-yl)-methanol. Purification is done by dissolution of the crude in 900 ml isopropanol/water 8/2 v/v, stirring at 80° C. until complete dissolution, then cool down to room temperature. Filtered at 0° C., the solid is washed with 150 ml of cold isopropanol. The cake is then dried under vacuum at 50° C., to afford 4-{[(2,4-dichloro-thiazol-5-yl)methyl]-isobutyl-amino}-piperidine-1-carboxylic acid t-butyl ester as a white crystalline powder, 293 g (78% yield for the two first steps). Mass spectrum (ion spray): m/z=422 (M+1); 1H NMR (250 MHz, CDCl3): δ=4.35 (2H, brd), 3.87 (2H, s), 2.80 (3H, m), 2.42 (2H,d), 1.86 (3H, m), 1.61 (11H, m), 1.06 (6H, d); 13C NMR (62 MHz, CDCl3): δ=155.02, 150.71, 137.29, 132.52, 79.95, 58.81, 58.44, 47.64, 43.93, 28.82, 28.03, 27.48, 21.03.