Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:42])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][CH2:15][C:16]3[CH:17]=[C:18]([C:22]4[C:27]([CH3:28])=[CH:26][C:25]([O:29][CH:30]5[CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31]5)=[CH:24][C:23]=4[CH3:41])[CH:19]=[CH:20][CH:21]=3)=[CH:13][C:8]=2[O:7][CH2:6]1.[F:43][C:44]([F:49])([F:48])[C:45]([OH:47])=[O:46]>ClCCl>[F:43][C:44]([F:49])([F:48])[C:45]([OH:47])=[O:46].[NH:32]1[CH2:33][CH:30]([O:29][C:25]2[CH:24]=[C:23]([CH3:41])[C:22]([C:18]3[CH:19]=[CH:20][CH:21]=[C:16]([CH2:15][O:14][C:12]4[CH:11]=[CH:10][C:9]5[C@H:5]([CH2:4][C:3]([O:2][CH3:1])=[O:42])[CH2:6][O:7][C:8]=5[CH:13]=4)[CH:17]=3)=[C:27]([CH3:28])[CH:26]=2)[CH2:31]1
Reactant: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(OC5CN(C(=O)OC(C)(C)C)C5)cc4C)c3)ccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(OC5CNC5)cc4C)c3)ccc21
Reaction time: 2 h

Procedure:
(S)-tert-Butyl 3-((3′-(((3-(2-methoxy-2-oxoethyl)-2,3-dihydrobenzofuran-6-yl)oxy)methyl)-2,6-dimethylbiphenyl-4-yl)oxy)azetidine-1-carboxylate 14b (100 mg, 0.17 mmol) was dissolved in 5 mL of dichloromethane, followed by addition of 1 mL of trifluoroacetic acid. The reaction solution was stirred for 2 hours. The resulting solution was concentrated under reduced pressure to obtain the crude title compound
Reaction SMILES: [CH:1]12[N:7]([C:8](=[O:48])[C:9]([C:12]3[CH:13]=[C:14]4[C:18](=[CH:19][CH:20]=3)[NH:17][C:16]([C:21]3[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([CH3:28])[CH:22]=3)=[C:15]4[C@H:29]([CH3:47])[CH2:30][NH:31][S:32]([C:35]3[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][C:36]=3[N+:44]([O-:46])=[O:45])(=[O:34])=[O:33])([CH3:11])[CH3:10])[CH:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[N:49]1[N:50]=[CH:51][N:52]([C:54]2[CH:59]=[CH:58][C:57]([CH2:60][CH2:61]O)=[CH:56][CH:55]=2)[CH:53]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[CH:4]12[N:7]([C:8](=[O:48])[C:9]([C:12]3[CH:13]=[C:14]4[C:18](=[CH:19][CH:20]=3)[NH:17][C:16]([C:21]3[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([CH3:28])[CH:22]=3)=[C:15]4[C@H:29]([CH3:47])[CH2:30][N:31]([CH2:61][CH2:60][C:57]3[CH:56]=[CH:55][C:54]([N:52]4[CH:53]=[N:49][N:50]=[CH:51]4)=[CH:59][CH:58]=3)[S:32]([C:35]3[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][C:36]=3[N+:44]([O-:46])=[O:45])(=[O:33])=[O:34])([CH3:10])[CH3:11])[CH:1]([CH2:2][CH2:3]1)[CH2:6][CH2:5]2
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(C(C)(C)C(=O)N4C5CCC4CC5)cc3c2[C@H](C)CNS(=O)(=O)c2ccc([N+](=O)[O-])cc2[N+](=O)[O-])c1
Reactant: OCCc1ccc(-n2cnnc2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1cc(C)cc(-c2[nH]c3ccc(C(C)(C)C(=O)N4C5CCC4CC5)cc3c2[C@H](C)CN(CCc2ccc(-n3cnnc3)cc2)S(=O)(=O)c2ccc([N+](=O)[O-])cc2[N+](=O)[O-])c1
Reaction time: 1.5 h
Yield: 99.6 %

Procedure:
To a solution of (S)-N-{2-[5-[2-(7-azabicyclo[2.2.1]hept-7-yl)-1,1-dimethyl 2-oxo-ethyl]-2-(3,5-dimethylphenyl)-1H-indol-3-yl]-propyl}-2,4-dinitrobenzenesulfonamide (0.197 g in 6 mL dry benzene:N,N-dimethylformamide, 2:1) was added 0.083 g 2-(4-[1,2,4]triazol-4-yl-phenyl)ethanol followed by 0.115 g triphenylphosphine and 0.069 mL of diethyl azodicarboxylate added dropwise. After 1.5 hours, the mixture was concentrated and the crude reaction product purified by flash chromatography on silica gel (methylene chloride:methanol, 95:5) to give the title compound (0.246 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3=[N:13][C:14]4[CH2:15][CH2:16][CH2:17][C:18](=[CH2:21])[C:19]=4[CH:20]=[C:11]3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.O.[OH:23]I(C1C=CC=CC=1)OS(C1C=CC(C)=CC=1)(=O)=O.FC1C=CC(N2C3=NC4CCCC(=C)C=4C=C3C(=O)N2)=CC=1>CO.OI(C1C=CC=CC=1)OS(C1C=CC(C)=CC=1)(=O)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]3[N:13]=[C:14]4[CH2:15][CH2:16][CH2:17][C:18](=[O:23])[CH2:21][C:19]4=[CH:20][C:11]=3[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: C=C1CCCc2nc3c(cnn3-c3ccc(F)cc3)cc21
Reactant: Cc1ccc(S(=O)(=O)OI(O)c2ccccc2)cc1
Agent: C=C1CCCc2nc3c(cc21)c(=O)[nH]n3-c1ccc(F)cc1
Solvent: CO
Solvent: O
Product: O=C1CCCc2nc3c(cnn3-c3ccc(F)cc3)cc2C1
Temperature: 19 °C
Reaction time: 1 h
Yield: 78.8 %

Procedure:
A flask was charged with 1-(4-fluorophenyl)-5-methylene-5,6,7,8-tetrahydro-1H-pyrazolo[3,4-b]quinoline (113, R1=4-Fluorophenyl) (44.0 g, 158 mmol), MeOH (1050 mL) and water (105 mL). [Hydroxy(tosyloxy)iodo]benzene (61.8 g, 158 mmol) was dissolved in MeOH (160 mL) then the solution was added dropwise to the stirred 1-(4-fluorophenyl)-5-methylene-5,6,7,8-tetrahydro-1H-pyrazolo[3,4-b]quinolone slurry. The internal temperature of the reaction mixture was maintained at about 18 to 20° C. during the addition. The addition was carried out over about 1 h. After about 90 min [hydroxy(tosyloxy)iodo]benzene (3.09 g, 7.88 mmol) was added and the mixture was stirred for about 1 h. A third portion of [hydroxy(tosyloxy)iodo]benzene (2.5 g, 6.37 mmol) was added then after about 15 min the reaction mixture was concentrated under reduced pressure to remove about 1 L solvent (˜70 torr, bath temp ˜40° C.). Water (1.5 L) was added to the mixture and the resulting slurry was stirred for about 4 h at rt. The solids were collected by filtration then the pad was washed with about 150 mL water. The material was air dried then dissolved in DCM (500 mL) then washed with a mixture of water (100 mL) with sat. aq. NaHCO3 (100 mL). The organic solution was dried over MgSO4, filtered and the filtrate concentrated to dryness under reduced pressure. The material was treated with DCM (100 mL) then the slurry was poured onto a filter funnel containing 500 gram silica gel pre-gelled with DCM. The pad was washed with DCM (500 mL) then 9:1 DCM/EtOAc (2 L). Filtrate containing desired product was concentrated under reduced pressure then the material was treated with DCM (50 mL) and heptane (250 mL). The solids were collected by filtration and washed with heptane (100 mL). The material was dried under vacuum at about 70° C. to yield 1-(4-fluorophenyl)-5,7,8,9-tetrahydrocyclohepta[b]pyrazolo[4,3-e]pyridin-6(1H)-one (114, R1=4-Fluorophenyl) (36.78 g, 79%). LC/MS, method 3, Rt=2.31 min, MS m/z 296 (M+H)+. 1H NMR (400 MHz, DMSO) δ 8.36 (s, 1H), 8.34-8.28 (m, 2H), 8.16 (s, 1H), 7.46-7.38 (m, 2H), 3.92 (s, 2H), 3.36-3.28 (m, 2H), 2.57 (t, J=6.9 Hz, 2H), 2.05-1.94 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][S:10][CH2:11][CH2:12][O:13][N:14]1[CH:22]=[N:21][C:20]2[C:15]1=[N:16][CH:17]=[N:18][C:19]=2[N:23]1C(=O)C2=CC=CC=C2C1=O)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].CNN>>[CH2:1]([O:3][P:4]([CH2:9][S:10][CH2:11][CH2:12][O:13][N:14]1[CH:22]=[N:21][C:20]2[C:15]1=[N:16][CH:17]=[N:18][C:19]=2[NH2:23])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]
Reactant: CCOP(=O)(CSCCOn1cnc2c(N3C(=O)c4ccccc4C3=O)ncnc21)OCC
Agent: CNN
Product: CCOP(=O)(CSCCOn1cnc2c(N)ncnc21)OCC
Reaction time: 1 h
Yield: 72.9 %

Procedure:
A solution of 9-[2-(diethoxyphosphorylmethylthio)ethoxy]-6-phthalimidopurine (0.56 g, 1.lmmol) was cooled to 0°-5° C. and treated with N-methylhydrazine (0.86 g, 1.8 mmol). The mixture was stirred for 1 hour, and then filtered and the solvent was removed in vacuo. The residue was purified by column chromatography on silica gel, using dichloromethane: methanol (97:3) as eluent, to give the title compound (0.3 g, 75%) as colourless crystals after b crystallisation from acetone, m.p. 93°-95° C.; γmax (MeOH) 260nm (ε 12670); υmax (KBr) 3360, 3280, 3140, 2995, 1685, 1610, 1570, 1480, 1410, 1370, 1330, 1300, and 1260cm-1 ; 6H [(CD3)2SO]1.25 (6H. t, J 8Hz 2 × CH3), 3.0 (2H, d, J 13Hz PCH2S), 3.1 (2H, t, J 7Hz, CH2O), 4.1 (4H, m, 2 × CH2), 4.6 (2H, t, J 7Hz, CH2S), 7.4 (2H, br.s, exchangeable with D2O, NH2), 8.15 (1H, s, 2-H), 8.4 (1H, s, 8-H) (Found: C, 39.84; H, 5.51; N, 19.26%; M+ 361.0981. C12H2O N5O4PS requires C, 39.88; H, 5.58; N, 19.38%; M+ 361.0974).
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:18](O)=O)=[N:9][O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[OH:35][N:36]=[C:37]([NH2:49])[C:38]1[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][C:39]=1[C:45]([F:48])([F:47])[F:46]>CN(C)C=O>[C:1]1([C:7]2[C:8]([C:18]3[O:35][N:36]=[C:37]([C:38]4[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][C:39]=4[C:45]([F:47])([F:46])[F:48])[N:49]=3)=[N:9][O:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1noc(-c2ccccc2)c1-c1ccccc1
Reactant: Cc1ccc(C(N)=NO)c(C(F)(F)F)c1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Cc1ccc(-c2noc(-c3noc(-c4ccccc4)c3-c3ccccc3)n2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.3 %

Procedure:
A 2 dram reaction vial containing a stir bar was charged with 4,5-diphenylisoxazole-3-carboxylic acid (17-B, 48.6 mg, 0.183 mmol), EDC (43.9 mg, 0.229 mmol), HOBT (35.1 mg, 0.229 mmol), and dimethylformamide (1 mL). The vial was flushed with dry nitrogen, sealed, and the reaction was stirred at room temperature for 30 minutes. N′-Hydroxy-4-methyl-2-(trifluoromethyl)benzimidamide (40.0 mg, 0.183 mmol) was introduced. The vial was flushed with dry nitrogen, sealed, stirred at room temperature for 30 minutes, and then placed on a reactor block set to 60° C. overnight. Water was added dropwise (−0.5 mL) until the solution remained cloudy, and then the reaction was cooled to room temperature. Additional water (5 mL) was added after cooling, and the reaction was placed in a sonicator bath for 60 min. A gummy solid formed on the side of the flask and stir bar. The aqueous solution was decanted and the residue washed with water and then partially dried under a stream of air. The gummy solid was dissolved in methanol (1-2 mL), transferred, and evaporated to dryness to give a pale yellow solid The pale yellow solid was purified by flash chromatography (12 g Isco silica gel). Elution with dichloromethane afforded the major product. The product containing fractions were evaporated to afford 5-(4,5-diphenylisoxazol-3-yl)-3-(4-methyl-2-(trifluoromethyl)phenyl)-1,2,4-oxadiazole (24 mg) MS M+1=448.1.
Reaction SMILES: C1([O:6][C:7]2[C:12]3[O:13][C:14]4[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=4[C:11]=3[C:10]([CH:23]=[O:24])=[CH:9][CH:8]=2)CCCC1>Br.C(O)(=O)C>[OH:6][C:7]1[C:12]2[O:13][C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=3[C:11]=2[C:10]([CH:23]=[O:24])=[CH:9][CH:8]=1
Reactant: O=Cc1ccc(OC2CCCC2)c2oc3ccc([N+](=O)[O-])cc3c12
Agent: Br
Solvent: CC(=O)O
Product: O=Cc1ccc(O)c2oc3ccc([N+](=O)[O-])cc3c12
Temperature: 0 °C
Yield: 0.1 %

Procedure:
4-cyclopentyloxy-8-nitro-1-formyl dibenzo[b,d]furan (200 mg, 0.530 mol) was heated in HBr (47% in acetic acid) (5 ml) in glacial acetic acid (10 ml) at 50° C. for 7–8 h. The reaction contents were poured in ice-water (200 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layer was washed with saturated sodium bicarbonate, and water and dried over anhydrous sodium sulfate. Removal of the organic solvent in vacuo afforded the crude product as a white solid (150 mg). The crude white solid was used as such without further purification. mp: >270° C.
Reaction SMILES: [C:1]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([NH:16][C:17]3[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=3)[N:14]=2)[N:9]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH:8]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[S:33]1[CH2:37][C:36](=[O:38])[NH:35][C:34]1=[O:39].C(O)(=O)C.N1CCCCC1>C(O)C>[C:1]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([CH:21]=[C:37]4[S:33][C:34](=[O:39])[NH:35][C:36]4=[O:38])=[CH:23][CH:24]=3)[N:14]=2)[N:9]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:31])([CH3:32])[CH3:30])[CH:8]=1)(=[O:6])[C:2]([CH3:4])([CH3:3])[CH3:5]
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Nc3ccc(C=O)cc3)nc12
Reactant: O=C1CSC(=O)N1
Solvent: C1CCNCC1
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Nc3ccc(C=C4SC(=O)NC4=O)cc3)nc12
Temperature: 80 °C
Yield: 77 %

Procedure:
To a 35 ml reaction vial 4-(7-pivaloyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl amino)benzaldehyde (0.200 g, 0.0004 mole) and thiazolidine-2,4-dione (0.155 g, 0.0105 mole) were taken in ethanol (10 ml). Piperidine acetate (3.3M solution in water) (3 ml) was added at RT. The reaction mixture was heated to 80° C. for 16 hrs. After completion of the reaction, ethanol was evaporated under reduced pressure and diluted with EtOAc. Organic layer was washed with water, dried over Na2SO4 and evaporated to get crude product which was purified using column purification by eluting the compound with 10-20% EtOAc in Hexanes to yield 0.170 g of 5-(4-(7-pivaloyl-5-((2-(trimethylsilyl)ethoxy)-methyl)-5H-pyrrolo[2,3-b]pyrazin-2-ylamino)benzylidene)thiazolidine-2,4-dione.
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[C:28]([C:30]#[N:31])[CH:27]=[CH:26][C:3]=1[NH:4][CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][CH:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:7][CH2:6]1.[CH:32](OC)(OC)OC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[C:30]([C:28]1[CH:27]=[CH:26][C:3]2[N:4]([CH:5]3[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][CH:13]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:7][CH2:6]3)[CH:32]=[N:1][C:2]=2[CH:29]=1)#[N:31]
Reactant: N#Cc1ccc(NC2CCN(CCC(c3ccccc3)c3ccccc3)CC2)c(N)c1
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: N#Cc1ccc2c(c1)ncn2C1CCN(CCC(c2ccccc2)c2ccccc2)CC1

Procedure:
A solution of 2-amino-4-cyano-1-N-[1-(3,3-diphenylpropyl)-piperidin-4-yl]aniline (prepared as described below) (60 mg, 0.15 mmol), trimethyl orthoformate (0.7 ml) and para-toluenesulphonic acid monohydrate (2 mg, 0.11 mmol) was stirred at 100° C. After 2.5 h the mixture was cooled and water (10 ml) was added. The solution was partitioned with EtOAc (2×40 ml) then the organics were combined, dried (MgSO4) and concentrated to give the title compound as an oil (58 mg, 0.15 mmol); MS: 421.
Reaction SMILES: [CH2:1]([N:5]([CH2:13][CH2:14][CH2:15][CH3:16])[C:6]1[CH:7]=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4].Cl[CH2:18][C:19](Cl)=[O:20]>C(Cl)(Cl)Cl>[CH2:1]([N:5]([CH2:13][CH2:14][CH2:15][CH3:16])[C:6]1[CH:11]=[CH:10][C:9]2[C:19](=[O:20])[C:18](=[C:18]3[C:19](=[O:20])[C:9]4[CH:10]=[CH:11][C:6]([N:5]([CH2:13][CH2:14][CH2:15][CH3:16])[CH2:1][CH2:2][CH2:3][CH3:4])=[CH:7][C:8]=4[O:12]3)[O:12][C:8]=2[CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(CCCC)c1cccc(O)c1
Reactant: O=C(Cl)CCl
Solvent: ClC(Cl)Cl
Product: CCCCN(CCCC)c1ccc2c(c1)OC(=C1Oc3cc(N(CCCC)CCCC)ccc3C1=O)C2=O

Procedure:
1.8 g (8.1 mmol) of 3-di-n-butylamino-phenol are dissolved in 20 ml of dry chloroform with exclusion of moisture. 0.7 ml (8.8 mmol) of chloroacetyl chloride is added dropwise with vigorous stirring. Silica gel (about 10 g in total) is then allowed to trickle in until a large proportion of the reaction solution has been absorbed, and the mixture is boiled under reflux for 15 hours. Finally, the solid is filtered off and washed with chloroform until the wash solution remains virtually colourless. The organic phases are combined. After the solvent has been stripped off on a rotary evaporator, 1.4 g of a dark brown, highly viscous crude product are obtained. Working up of the crude product by column chromatography over silica gel using chloroform as the solvent gives the oxindigo colorant as a red-violet fraction in the first runnings. After the chloroform has been stripped off, the resulting colorant is dried under an oil pump vacuum at 75° C. for 5 hours.
Reaction SMILES: C(OC([NH:8][C:9]1[NH:37][CH2:36][C:35]2[CH:38]=[C:39]([Cl:40])[C:32](=[C:33]([Cl:41])[CH:34]=2)[NH:31][C:30](=[O:42])[CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26][CH2:25][CH:24]=[CH:23][CH2:22][O:21][C:20]2[CH:50]=[CH:51][C:17](=[CH:18][CH:19]=2)[C:16]2[C:12](=[C:13]([CH3:52])[S:14][N:15]=2)[C:11](=[O:53])[N:10]=1)=O)(C)(C)C.[H][H]>CO.[Pd]>[NH2:8][C:9]1[NH:37][CH2:36][C:35]2[CH:34]=[C:33]([Cl:41])[C:32](=[C:39]([Cl:40])[CH:38]=2)[NH:31][C:30](=[O:42])[CH2:29][NH:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][O:21][C:20]2[CH:19]=[CH:18][C:17](=[CH:51][CH:50]=2)[C:16]2[C:12](=[C:13]([CH3:52])[S:14][N:15]=2)[C:11](=[O:53])[N:10]=1
Reactant: Cc1snc2c1C(=O)N=C(NC(=O)OC(C)(C)C)NCc1cc(Cl)c(c(Cl)c1)NC(=O)CN(C(=O)OC(C)(C)C)CCCC=CCOc1ccc-2cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1snc2c1C(=O)N=C(N)NCc1cc(Cl)c(c(Cl)c1)NC(=O)CNCCCCCCOc1ccc-2cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The intermediate (20 mg) from Example 4, Step 4(C) was dissolved in methanol (4 mL), followed by the addition of 10-20 mg of 5% Pd/C. Hydrogen was introduced with a balloon and the reaction mixture was stirred at room temperature for 30 min. (longer reaction time for reaction at larger scale). The reaction mixture was filtered through Celite to remove the catalyst. Solvent was evaporated in vacuo to give a crude product, which was subjected to the protocol described in Example 1, Step 1(D) to yield the title compound.
Reaction SMILES: [C:1]([CH2:3][CH2:4][NH:5][C:6](=O)[C@H:7]([C:30]1[CH:31]=[C:32]([CH3:36])[CH:33]=[CH:34][CH:35]=1)[CH2:8][C:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[N:11]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[N:10]=1)#[N:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C[Si]([N:75]=[N+:76]=[N-:77])(C)C.N([O-])=O.[Na+].[N+]([O-])([O-])=O.[NH4+]>O.C(#N)C>[Cl:21][C:16]1[CH:15]=[C:14]([C:12]2[N:11]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[N:10]=[C:9]([CH2:8][C@H:7]([C:6]3[N:5]([CH2:4][CH2:3][C:1]#[N:2])[N:77]=[N:76][N:75]=3)[C:30]3[CH:31]=[C:32]([CH3:36])[CH:33]=[CH:34][CH:35]=3)[CH:13]=2)[CH:19]=[CH:18][C:17]=1[Cl:20]
Reactant: COc1ccc(-n2nc(C[C@H](C(=O)NCCC#N)c3cccc(C)c3)cc2-c2ccc(Cl)c(Cl)c2)cc1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: O=N[O-]
Agent: O=[N+]([O-])[O-]
Solvent: O
Solvent: CC#N
Product: COc1ccc(-n2nc(C[C@@H](c3cccc(C)c3)c3nnnn3CCC#N)cc2-c2ccc(Cl)c(Cl)c2)cc1
Temperature: 25 °C
Yield: 50.1 %

Procedure:
A 3-neck round-bottom flask was charged with (S)-N-(2-cyano-ethyl)-3-[5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionamide (4.0 g, 7.5 mmol, 1.0 equiv) and triphenyl phosphine (4.91 g, 18.8 mmol, 2.5 equiv) under nitrogen. Acetonitrile was added, and the mixture was stirred at room temperature until all of the solids dissolved. The solution was then cooled to 0° C., and diisopropyl azodicarboxylate (3.79 mL, 18.8 mmol, 2.5 equiv) was added slowly via syringe. After the resulting mixture had stirred for 5 min, trimethylsilyl azide (3.0 mL, 22.5 mmol, 3 equiv) was added via syringe over 20 min. The reaction mixture was allowed to warm to room temperature and was stirred for 30 min, and then was stirred at 50° C. for 14 h. The mixture was cooled to room temperature, then to 0° C., and a solution of sodium nitrite (685 mg) in water (3.3 mL) was added. After 20 min a solution of cerric ammonium nitrate (5.5 g) in water (15.5 mL) was added, and the resulting mixture was stirred for 30 min. The mixture was then added to water (200 mL), and the resulting solution was extracted with dichloromethane (2×100 mL). The combined extracts were washed with brine (100 mL), dried (Na2SO4), and concentrated under reduced pressure. The crude residue was purified by flash chromatography (25% ethyl acetate/dichloromethane) yielding the desired protected tetrazole (2.1 g, 50%). HPLC: Rt=8.18 (Method A). MS (ESI): mass calculated for C29H25Cl2N7O, 557.15; m/z found, 558.3 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.30 (d, J=8.2 Hz, 1H), 7.28-7.25 (m, 3H), 7.17-7.15 (m, 3H), 7.06 (d, J=9.0 Hz, 2H), 6.89-6.86 (m, 3H), 6.24 (s, 1H), 4.75 (dd, J=10.2, 5.3 Hz, 1H), 4.45-4.43 (m, 2H), 3.92 (dd, J=15.2, 10.2 Hz, 1H), 3.83 (s, 3H), 3.42 (dd, J=15.2, 5.3 Hz, 1H), 2.85-2.75 (m, 1H), 2.53-2.49 (m, 1H), 2.34 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH2:10][C@H:9]1[CH2:23][NH:24][CH2:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[F:33])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH2:10][C@H:9]1[CH2:23][N:24]([CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[F:33])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(CS[C@@H]2C[C@@H](CNCc3cc(F)ccc3F)N(C(=O)OC(C)(C)C)C2)cc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(CS[C@@H]2C[C@@H](CN(CC(=O)OC(C)(C)C)Cc3cc(F)ccc3F)N(C(=O)OC(C)(C)C)C2)cc1
Yield: 104.9 %

Procedure:
6.94 g (14.5 mmol) (2S,4R)-2-[(2,5-difluoro-benzylamino)-methyl]-4-(4-methoxy-benzylsulfanyl)-pyrrolidine-1-carboxylic acid tert-butyl ester were dissolved in 170 ml acetonitrile and treated with 3 ml (20.3 mmol, 1.4 eq) t-butyl bromoacetate and 18.6 g (134.9 mmol, 9.3 mmol) K2CO3 at RT for 2d. The solid was removed by filtration, and the organic phase was washed with water and brine, dried over Na2SO4 and evaporated, yielding 9.02 g (quant) (2S,4R)-2-[[tert-butoxycarbonylmethyl-(2,5-difluoro-benzyl)-amino]-methyl]-4-(4-methoxy-benzylsulfanyl)-pyrrolidine-1-carboxylic acid tert-butyl ester as orange oil, MS: 593 (MH+).
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH:34]5[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]5)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)S(O[CH2:46][CH:47]([F:49])[F:48])(=O)=O.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH:34]5[CH2:39][CH2:38][N:37]([CH2:46][CH:47]([F:49])[F:48])[CH2:36][CH2:35]5)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OC1CCNCC1
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OC1CCN(CC(F)F)CC1
Yield: 4.6 %

Procedure:
The title compound was prepared as described in Example 103C, using 1-(5-tert-butylisoxazol-3-yl)-3-{3-[6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-yloxy]phenyl}urea (0.213 g, 0.4 mmol), 2,2-difluoroethyl trifluoromethanesulfonate (0.128 g. 0.6 mmol), and N,N-diisopropylethylamine (0.5 mL) in CH2Cl2 (10 mL) at room temperature for 4 hours, which was purified by silica gel chromatography with EtOAc/hexane as eluants to afford 1-(5-tert-butylisoxazol-3-yl)-3-(3-{7-[1-(2,2-difluoroethyl)piperidin-4-yloxy]-6-methoxyquinazolin-4-yloxy}phenyl)urea as a solid (0.011 g, 4%). 1H NMR (300 MHz, CDCl3) δ 9.45 (s, 1H), 8.61 (s, 1H), 7.66 (t, 1H), 7.55 (s, 1H), 7.31-7.44 (m, 4H), 7.01 (d, 1H), 5.90 (tt, 1H), 5.81 (s, 1H), 4.58 (m, 1H), 4.04 (s, 3H), 2.93 (m, 2H), 2.80 (td, 2H), 2.53 (m, 2H), 2.15 (m, 2H), 2.00 (m, 2H), 1.33 (s, 9H); LC-MS (ESI) m/z 597 (M+H)+.
Reaction SMILES: [S:1]([NH2:5])([NH2:4])(=[O:3])=[O:2].Cl.[Cl:7][CH2:8][CH2:9][C:10]#[N:11]>C(OCC)C>[ClH:7].[S:1]([NH:5][C:10](=[NH:11])[CH2:9][CH2:8][Cl:7])(=[O:3])(=[O:2])[NH2:4]
Reactant: NS(N)(=O)=O
Reactant: N#CCCCl
Agent: Cl
Solvent: CCOCC
Product: N=C(CCCl)NS(N)(=O)=O
Temperature: 0 °C

Procedure:
To a stirred suspension of 9.61 g. (0.10 mole) of sulfamide in 30 ml (34 g., 0.38 mole) of 3-chloropropionitrile hydrogen chloride gas is introduced, as described in Example 1. After cooling with ice water for one hour the reaction mixture is diluted with 30 ml of dry ethyl ether, the product is filtered off, washed twice with acetone and dried.