Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[NH:7][C:6]([CH:12]([C:17]([CH3:22])([CH3:21])[CH:18]([CH3:20])[CH3:19])[O:13][SiH:14]([CH3:16])[CH3:15])=[CH:5]2.[H-].[Na+].[C:25]([O:29][C:30]([N:32]1[CH2:36][C@H:35]([CH3:37])OS1(=O)=O)=[O:31])([CH3:28])([CH3:27])[CH3:26]>CN(C)C=O>[C:25]([O:29][C:30](=[O:31])[NH:32][CH2:36][C@H:35]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([Br:1])=[C:10]([CH3:11])[CH:9]=2)[CH:5]=[C:6]1[CH:12]([C:17]([CH3:21])([CH3:22])[CH:18]([CH3:19])[CH3:20])[O:13][SiH:14]([CH3:15])[CH3:16])[CH3:37])([CH3:28])([CH3:27])[CH3:26]
Reactant: Cc1cc2[nH]c(C(O[SiH](C)C)C(C)(C)C(C)C)cc2cc1Br
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)S(=O)(=O)O1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc2c(cc1Br)cc(C(O[SiH](C)C)C(C)(C)C(C)C)n2[C@H](C)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.9 %

Procedure:
To a solution of 0.95 g 5-bromo-2-[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxymethyl]-6-methyl-1H-indole in 10 ml N,N-dimethylformamide was added 0.143 g sodium hydride 55–65% in oil and the mixture was stirred 30 min at room temperature. To the resulting mixture was added (S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester (0.703 g) and the mixture was stirred 2 h at room temperature. The reaction mixture was partitioned between water and ethyl acetate. The phases were separated and the organic phase was washed with 10% citric acid and brine, dried over magnesium sulfate and purified by chromatography on silica gel with hexane:ethyl acetate=5:1 to yield 0.789 g (R)-(2-{5-bromo-2-[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxymethyl]-6-methyl-indol-1-yl}-propyl)-carbamic acid tert-butyl ester as a slightly yellow oil. ISP-MS: M+H=541.3
Reaction SMILES: CC1C(CCC(O)=O)=C(CC2NC(/C=C3/C(C=C)=C(C)C(N/3)=O)=C(C)C=2CCC(O)=O)NC=1/C=C1/C(C)=C(C=C)C(N/1)=O.[CH3:44][CH2:45][C:46]1[C:68]([CH3:69])=[C:67]2[NH:70][C:47]=1[CH:48]=[C:49]1[N:102]=[C:101]3[C:51]([C:52]([C@H:54]([C:103]([O:105][CH3:106])=[O:104])[C:55]3=[C:56]3[N:60]=[C:59]([CH:61]=[C:62]4[NH:71][C:65](=[CH:66]2)[C:64]([CH:72]=[CH2:73])=[C:63]4[CH3:74])[C@@H:58]([CH3:75])[C@@H:57]3[CH2:76][CH2:77][C:78]([O:80][CH2:81]/C=C(/CCC[C@@H](CCC[C@@H](CCCC(C)C)C)C)\C)=[O:79])=[O:53])=[C:50]1[CH3:107].S(=O)(=O)(O)O.ClCCl>CO>[CH3:44][CH2:45][C:46]1[C:47]2=[N:70][C:67](=[CH:66][C:65]3[NH:71][C:62]([CH:61]=[C:59]4[CH:58]([CH3:75])[CH:57]([CH2:76][CH2:77][C:78]([O:80][CH3:81])=[O:79])[C:56]([C:55]5[CH:54]([C:103]([O:105][CH3:106])=[O:104])[C:52](=[O:53])[C:51]6[C:101]=5[NH:102][C:49]([C:50]=6[CH3:107])=[CH:48]2)=[N:60]4)=[C:63]([CH3:74])[C:64]=3[CH:72]=[CH2:73])[C:68]=1[CH3:69]
Reactant: C=Cc1c(C)c2cc3nc(c4c5nc(cc6[nH]c(cc1[nH]2)c(C)c6CC)C(C)=C5C(=O)[C@@H]4C(=O)OC)[C@@H](CCC(=O)OC/C=C(\C)CCC[C@H](C)CCC[C@H](C)CCCC(C)C)[C@@H]3C
Agent: C=CC1=C(C)/C(=C/c2[nH]c(Cc3[nH]c(/C=C4\NC(=O)C(C)=C4C=C)c(C)c3CCC(=O)O)c(CCC(=O)O)c2C)NC1=O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CO
Product: C=Cc1c(C)c2cc3nc(c4c5[nH]c(cc6nc(cc1[nH]2)C(C)=C6CC)c(C)c5C(=O)C4C(=O)OC)C(CCC(=O)OC)C3C

Procedure:
The green filtrate was evaporated and purified by flash chromatography on Grade V neutral Alumina, eluting first with n-hexane to remove a fast running yellow band and then with dichloromethane to obtain the major blue/gray peak containing pheophytin-a. Treatment of pheophytin-a with 500 ml sulfuric acid in methanol for 12 hours at room temperature in the dark under nitrogen was followed by dilution with dichloromethane. The reaction mixture was rinsed with water and then 10% aqueous sodium bicarbonate and the organic layer was dried, evaporated, and the residue recrystallized from dichloromethane/methanol to obtain 1.8 gm methyl pheophorbide-a. Methyl pheophorbide-a appears to be inactive in the in vivo tumorcidal activity assay when injected at a dose of 5 mg/kg.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH2:11]([OH:15])[CH2:12][C:13]#[CH:14]>C(N(CC)CC)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:14]#[C:13][CH2:12][CH2:11][OH:15])([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccccc1Br
Reactant: C#CCCO
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccccc1C#CCCO
Reaction time: 16 h
Yield: 78.5 %

Procedure:
A solution of o-bromonitrobenzene (8.1 g, 0.04 mol) in 160 ml of triethylamine, under nitrogen, is treated sequentially with bis(triphenylphosphine)palladium(II)chloride (0.28 g, 0.4 mmol), 3-butyne-1-ol (2.81 g, 0.04 mol) and copper(I)iodide (0.15 g, 0.8 mmol), stirred for about 16 hours and filtered. The filtercake is washed with toluene. The filtrates are combined and concentrated in vacuo to give the title product as a dark oil, 6.0 g, 78.5% yield, identified by NMR and mass spectral analyses.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[CH2:6][N:7]([CH3:25])[C:8](=[O:24])[C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][C:12]([CH2:22][OH:23])=[N:11][CH:10]=1.O[C:36]1[CH:37]=[C:38]([C:42]([F:45])([F:44])[F:43])[CH:39]=[CH:40][CH:41]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.C(OCC)(=O)C>[F:31][C:29]([F:32])([F:30])[C:27]1[CH:26]=[C:5]([CH:4]=[C:3]([C:2]([F:33])([F:1])[F:34])[CH:28]=1)[CH2:6][N:7]([CH3:25])[C:8](=[O:24])[C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][C:12]([CH2:22][O:23][C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:45])([F:44])[F:43])[CH:37]=2)=[N:11][CH:10]=1
Reactant: Cc1ccccc1-c1cc(CO)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccccc1-c1cc(COc2cccc(C(F)(F)F)c2)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 58.2 %

Procedure:
A solution of 80 mg (0.17 mmol) N-(3,5-bis-trifluoromethyl-benzyl)-6-hydroxymethyl-N-methyl-4-o-tolyl-nicotinamide (Example 7), 0.027 ml (0.22 mmol) 3-hydroxybenzotrifluoride, 47 mg (0.17 mmol) triphenylphosphine and 32 mg (0.17 mmol) diethyl azodicarboxylate in 2 ml tetrahydrofuran was stirred at room temperature over night. The reaction mixture was diluted with ethyl acetate and washed with 1N aqueous sodium hydroxide solution. The aqueous layer was extracted with three portions of ethyl acetate. The combined organic extracts were dried with sodium sulfate and concentrated. Column chromatography afforded 62 mg (60%) of the title compound as a light yellow amorphous mass.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[N:8][CH:7]=[C:6]2[CH2:13][C:14](O)=O.CCN(C(C)C)C(C)C.[NH2:26][C:27]1[C:28](=[O:40])[N:29]([CH3:39])[C:30](=[O:38])[N:31]([CH2:34][CH:35]([CH3:37])[CH3:36])[C:32]=1[NH2:33]>C(#N)C>[CH2:34]([N:31]1[C:32]2[N:33]=[C:14]([CH2:13][C:6]3[C:5]4[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=4)[CH:9]=[N:8][CH:7]=3)[NH:26][C:27]=2[C:28](=[O:40])[N:29]([CH3:39])[C:30]1=[O:38])[CH:35]([CH3:37])[CH3:36]
Reactant: COc1ccc2cncc(CC(=O)O)c2c1
Reactant: CC(C)Cn1c(N)c(N)c(=O)n(C)c1=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2cncc(Cc3nc4c([nH]3)c(=O)n(C)c(=O)n4CC(C)C)c2c1
Temperature: 25 °C

Procedure:
A suspension of (6-methoxy-isoquinolin-4-yl)-acetic acid (3.5 g, 13.82 mmol) in acetonitrile (70 ml) is treated sequentially with Hunig's base (6.15 ml, 36 mmol), O(7-benzotriazo-1-yl)-N,N,N′, N′-tetramethyluronium hexafluorophosphate (6.29 g, 16.6 mmol) and 5,6-diamino-1-isobutyl-3-methyl-1H-pyrimidine-2,4-dione (3.22 g, 15.2 at mmol) while the solution is stirred at room temperature. The reaction is stirred at ambient temperature for 2 h, prior to evaporation of the solvent. The residue is triturated with ethyl acetate (50 ml) filtered and washed with ethyl acetate and then dried at 50° C. under reduced pressure. The resulting intermediate is suspended in a mixture of methanol (30 ml) and 4M aqueous sodium hydroxide (60 ml) and heated at 80° C. for 45 minutes. This suspension is neutralised with acetic acid and cooled to 0-5° C. overnight. The resultant solid is collected by filtration, and washed with methanol/water 1:9 (30 ml) followed by methanol (30 ml). Drying under high vacuum at 50° C. affords 3-isobutyl-8-(6-methoxy-isoquinolin-4-ylmethyl)-1-methyl-3,7-dihydro-purine-2,6-dione, [MH]+ 394.5.
Reaction SMILES: BrN1C(=[O:7])CCC1=O.[O:9]=[C:10]1[CH2:16][N:15]=[C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13]2[CH:23]=[CH:24][CH:25]=[CH:26][C:12]=2[N:11]1[CH2:27][C:28]([F:31])([F:30])[F:29].FC(F)(F)C(O)=O>C(Cl)(Cl)(Cl)Cl>[OH:7][CH:16]1[N:15]=[C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13]2[CH:23]=[CH:24][CH:25]=[CH:26][C:12]=2[N:11]([CH2:27][C:28]([F:31])([F:29])[F:30])[C:10]1=[O:9]
Reactant: O=C1CN=C(c2ccccc2)c2ccccc2N1CC(F)(F)F
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: O=C1C(O)N=C(c2ccccc2)c2ccccc2N1CC(F)(F)F
Reaction time: 0.25 h

Procedure:
N-Bromosuccinimide (0.335 g, 1.88 mmol) was added to a solution of 2-oxo-5-phenyl-1-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-1,4-benzodiazepine (H. G. Selnick et al., J. Med. Chem., 1997, 40, 3865-3868) (0.500 g, 1.57 mmol) in carbon tetrachloride (20 mL) at room temperature. After 15 min, trifluoroacetic acid (1.0 mL) was added, and the reaction refluxed for 5 h. The reaction was cooled and concentrated. The residue was dissolved in 5% aqueous sodium acetate (15 mL) and acetone (10 mL) and stirred overnight. The reaction was concentrated and worked up, and the crude product purified by chromatography (silica gel, 0-30% ethyl acetate in hexane gradient elution), providing the title compound. MS 335 (M+1) 1H NMR (500 MHz, CDCl3) □ 7.92-7.30 (9H, m), 5.21 (dq, J=15, 8 Hz, 1H), 5.07 (d, J=10 Hz, 0.5H), 4.51 (d, J=10 Hz, 0.5H), 4.22 (t, dq, J=15, 8 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[CH2:15]=O.[NH2:17][C:18]1[N:19]([CH3:30])[N:20]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:21](=[O:23])[CH:22]=1>>[OH2:2].[NH2:17][C:18]1[N:19]([CH3:30])[N:20]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:21](=[O:23])[C:22]=1[CH2:15][N:12]1[CH2:13][CH2:14][N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH2:10][CH2:11]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: C=O
Reactant: Cn1c(N)cc(=O)n1-c1ccccc1
Product: COc1ccccc1N1CCN(Cc2c(N)n(C)n(-c3ccccc3)c2=O)CC1
Product: O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 1-(2-methoxyphenyl)piperazine (2.16 g), 37-40% aqueous formaldehyde solution (0.8 ml) and industrial methylated spirit (27 ml) was stirred at ambient temperature under nitrogen for 18 hours, then a slurry of 3-amino-2-methyl-1-phenyl-3-pyrazolin-5-one (2.14 g) in industrial methylated spirit (54 ml) was added in one portion. The stirred mixture was heated under reflux for 24 hours, allowed to cool to ambient temperature, and the resulting solid was collected by filtration, washed with industrial methylated spirit, and dried in vacuo at 50° C. to give 3-amino-4-[4-(2-methoxyphenyl)piperazin-1-ylmethyl]-2-methyl-1-phenyl-3-pyrazolin-5-one monohydrate as an off-white solid (3.2 g), m.p. 133-136° C.
Reaction SMILES: [C:1]1([S:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:19][CH2:20][OH:21])[CH:17]=3)[NH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:22]1(C)[C:23]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:25]=[CH:26][CH:27]=1.N1C=CC=C[CH:34]=1>>[CH3:34][C:26]1[CH:27]=[CH:22][C:23]([S:28]([O:21][CH2:20][CH2:19][C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][CH:15]=2)[NH:12][CH:11]=[C:10]3[S:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:8])=[O:9])(=[O:29])=[O:30])=[CH:24][CH:25]=1
Reactant: Cc1ccccc1S(=O)(=O)Cl
Reactant: c1ccncc1
Reactant: O=S(=O)(c1ccccc1)c1c[nH]c2ccc(CCO)cc12
Product: Cc1ccc(S(=O)(=O)OCCc2ccc3[nH]cc(S(=O)(=O)c4ccccc4)c3c2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 95 %

Procedure:
To a solution of 2-[3-(phenylsulfonyl)-1H-indol-5-yl]ethanol (0.88 g, 2.91 mmol) in anhydrous pyridine (15 mL) at 0° C. was added toluenesulfonyl chloride (0.58 g, 3.05 mmol). The solution was stirred for 12 hours at room temperature. The mixture was partitioned between ethyl acetate and H2O, and the aqueous layer was extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with 2 M HCl, (2×25 mL), brine, dried (MgSO4), filtered and concentrated under reduced pressure. Silica gel chromatography (50% ethyl acetate/dichloromethane) gave the title compound as a white solid (1.3 g, 95%). Mp: 60-63° C. MS (ES−): 454 (M−H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([Cl:16])[N:3]=1.[CH:17]1([CH:22]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:23]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[O:24])[CH2:21][CH2:20][CH2:19][CH2:18]1>C(O)CC(C)C>[ClH:16].[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([N:28]2[CH2:29][CH2:30][N:25]([C:23](=[O:24])[CH:22]([CH:17]3[CH2:18][CH2:19][CH2:20][CH2:21]3)[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH2:26][CH2:27]2)[N:3]=1
Reactant: O=C(C(c1ccccc1)C1CCCC1)N1CCNCC1
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Solvent: CC(C)CCO
Product: COc1cc2nc(N3CCN(C(=O)C(c4ccccc4)C4CCCC4)CC3)nc(N)c2cc1OC
Product: Cl
Yield: 44.9 %

Procedure:
To 25 ml of isopentanol were added 1.2 g of 4-amino-2-chloro-6,7-dimethoxyquinazoline and 1.63 g of 1-(2-cyclopentyl-2-phenylacetyl)piperazine, and the resulting mixture was heated under reflux for 4 hours. The crystals thus produced were collected by filtration and neutralized by the addition of a 10% w/w aqueous solution of sodium hydroxide. The resulting mixture was extracted with chloroform and the extract was charged into a silica gel chromatography column and eluted with chloroform. A 10% w/w solution of hydrogen chloride in ethanol was added to the eluate and the crystals thus produced were collected by filtration, giving 1.15 g of the desired Compound No. 79 hydrochloride in the form of pale yellow powdery crystals melting at 222°-224° C. (with decomposition).
Reaction SMILES: [NH2:1][C:2](=[N:38][OH:39])[CH2:3][O:4][NH:5][C:6]([CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[N:10]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]2[NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH:9]1[C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=1[Cl:37])=[O:7].N1C=CC=CC=1.Cl[C:47](=O)[C:48]([O:50][CH3:51])=[O:49]>ClC(Cl)C>[Cl:37][C:31]1[CH:32]=[C:33]([Cl:36])[CH:34]=[CH:35][C:30]=1[CH:9]1[CH:8]([C:6]([NH:5][O:4][CH2:3][C:2]2[N:1]=[C:47]([C:48]([O:50][CH3:51])=[O:49])[O:39][N:38]=2)=[O:7])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[N:10]1[CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]1[NH:25][S:26]([CH3:29])(=[O:27])=[O:28]
Reactant: COC(=O)C(=O)Cl
Reactant: CS(=O)(=O)NC1CCCCC1N1C(=O)c2ccccc2C(C(=O)NOCC(N)=NO)C1c1ccc(Cl)cc1Cl
Solvent: c1ccncc1
Solvent: CC(Cl)Cl
Product: COC(=O)c1nc(CONC(=O)C2c3ccccc3C(=O)N(C3CCCCC3NS(C)(=O)=O)C2c2ccc(Cl)cc2Cl)no1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of 1000 mg of (3RS,4RS)—N-[2-amino-2-(hydroxyimino)ethoxy]-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(mesyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide in 26 ml of dichloroethane was added dropwise 0.4 ml of pyridine, and then 0.23 ml of methyl chloro(oxo)acetate was added dropwise thereto under ice-cooling, followed by stirring at 0° C. for 10 minutes, at room temperature for 20 minutes, and at 80° C. for 2 hours. The reaction solution was cooled to room temperature, washed with 0.1 M hydrochloric acid and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:chloroform-methanol) to obtain 670 mg of methyl 3-{[({[(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(mesyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)oxy]methyl}-1,2,4-oxadiazole-5-carboxylate as a white amorphous substance.
Reaction SMILES: [ClH:1].[CH2:2]([NH:6][CH2:7][C@@H:8]([C@H:10]([C@@H:12]([C@@H:14]([CH2:16][OH:17])[OH:15])[OH:13])[OH:11])[OH:9])[CH2:3][CH2:4][CH3:5].[OH-].[Na+]>O>[ClH:1].[CH2:2]([NH:6][CH2:7][C@@H:8]1[O:9][C@:14]([OH:15])([CH2:16][OH:17])[C@@H:12]([OH:13])[C@@H:10]1[OH:11])[CH2:3][CH2:4][CH3:5]
Reactant: CCCCNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCNC[C@@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O
Temperature: 15 °C
Reaction time: 23 h
Yield: 80 %

Procedure:
A reaction solution is prepared by adding 109 ml of a bulk solution of N-n-butylglucamine hydrochloride (prepared in Example 1) with a concentration of 500 gm/L by HPLC to 460 ml of water in a 1-L bioreactor. The solution is adjusted to pH 5 by adding dilute sodium hydroxide and cooled to about 15° C. A total of 30 gm (wet weight) of washed G. oxydans cell paste is added and the reaction mixture is agitated (500 rpm) and aerated (0.5 vvm) while controlling the temperature at 15° C. and pH at 5. After 23 hours, the HPLC assay indicates that over 99% of the substrate has been converted for a 80% yield of 6-n-butylamino-6-deoxy-α-L-sorbo-furanose hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:22](=[O:23])[N:21]([CH2:24][CH3:25])[C:12]2[N:13]=[C:14](S(C)(=O)=O)[N:15]=[CH:16][C:11]=2[CH:10]=1.[CH2:26]([O:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1)[CH3:27]>C(O)(=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:22](=[O:23])[N:21]([CH2:24][CH3:25])[C:12]2[N:13]=[C:14]([NH:33][C:32]3[CH:34]=[CH:35][C:29]([O:28][CH2:26][CH3:27])=[CH:30][CH:31]=3)[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: CCOc1ccc(N)cc1
Reactant: CCn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(S(C)(=O)=O)nc21
Solvent: CC(=O)O
Solvent: O
Product: CCOc1ccc(Nc2ncc3cc(-c4c(Cl)cccc4Cl)c(=O)n(CC)c3n2)cc1

Procedure:
A mixture of 0.150 g (0.38 mmol) of 6-(2,6-dichlorophenyl)-8-ethyl-2-methanesulfonyl-8H-pyrido[2,3-d]pyrimidin-7-one of Example 68 and 0.500 g (3.60 mmol) of 4-ethoxyaniline was fused in a 160° C. oil bath for 10 minutes. The dark violet melt was cooled and dissolved in 1 mL of warm glacial acetic acid. This solution was diluted to 10 mL volume with water to precipitate a solid. The solid was filtered, washed well with water, and dried; wt 0.140 g. Purification was effected by filtration of an ethyl acetate solution through a layer of silica gel and washing the silica gel with ethyl acetate. The filtrate was concentrated to 2 mL volume and 2 mL of petroleum ether was added. The crystals that separated on inducement were filtered and washed with ether; wt 0.094 g; mp 192°-194° C.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[S:9])=[CH:3][CH:2]=1.[CH3:17][I:18]>C(O)C>[IH:18].[CH3:17][S:9][C:8](=[N:7][C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CI
Reactant: S=C(Nc1ccccc1)Nc1ccccc1
Solvent: CCO
Product: CSC(=Nc1ccccc1)Nc1ccccc1
Product: I

Procedure:
A mixture of 22.8 gm. (0.1 mole) of thiocarbanilide and 17 gm. (0.12 mole) of methyl iodide in 400 ml. of ethanol is heated at reflux for 6 hours. The solvent is evaporated and residue is crystallized from ethyl acetate; 29 gm. (78%), m.p. 155°-156°.
Reaction SMILES: [Br:1][C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]([CH:10]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]([Cl:26])[CH:20]=2)[C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[C:4]([C:27](O)=[O:28])[CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>O1CCOCC1.CCOC(C)=O>[Br:1][C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]2[CH:10]([C:11]3[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=3)[N:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([Cl:26])[CH:20]=3)[C:27](=[O:28])[C:4]=2[CH:3]=1
Reactant: CC(C)n1c(Br)cc(C(=O)O)c1C(Nc1ccc(F)c(Cl)c1)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1COCCO1
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: CC(C)n1c(Br)cc2c1C(c1ccc(Cl)cc1)N(c1ccc(F)c(Cl)c1)C2=O
Temperature: 80 °C

Procedure:
A mixture of 5-bromo-2-[(3-chloro-4-fluoro-phenylamino)-(4-chloro-phenyl)-methyl]-1-isopropyl-1H-pyrrole-3-carboxylic acid (Step D1) (1.483 mmol), HATU (1.632 mmol) and NMM (4.45 mmol) in dioxane (75 mL) was heated at 80° C. for 17 h. After cooling to rt, the reaction mixture was diluted with EtOAc and washed with a saturated aqueous solution of NaHCO3. The aqueous phase was extracted with EtOAc (2×). The combined organic phases were washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified using a RediSep® silica gel column to afford the title compound as a light-yellow solid. tR: 5.31 min (HPLC 2); ESI-MS: tR=1.40 min, [M+H]+481/483/485 (LC-MS 1); TLC: Rf=0.27 (1:3 EtOAc/hexanes).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]4[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=4)[O:24][CH2:25][C:26]([OH:28])=O)[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:74][C:75]([CH3:79])([CH3:78])[CH2:76][NH2:77]>C(Cl)Cl.CN(C=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]4[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=4)[O:24][CH2:25][C:26]([NH:77][CH2:76][C:75]([CH3:79])([CH3:78])[CH3:74])=[O:28])[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: O=C(O)COc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1
Reactant: CC(C)(C)CN
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)CNC(=O)COc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1
Reaction time: 0.5 h

Procedure:
A suspension of 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetic acid (70 mg, 0.14 mmol), PyBOP® (40 mg, 0.077 mmol), DIEA (24 μL, 0.14 mmol) in dry CH2Cl2:DMF (2:0.1 mL) was stirred at RT for 15 minutes. To this solution of activated acid was added 2,2-dimethylpropan-1-amine (7.9 mg, 0.091 mmol). After 30 minutes, 1.0 equivalent of DIEA and 0.55 equivalents of PyBOP® were added. After stirring the solution for 15 minutes, 0.65 equivalents of 2,2-dimethylpropan-1-amine were added and the mixture was stirred for an additional 30 minutes. The solvent was removed in vacuo and the crude product was purified using prep HPLC (25-50—90 mins) to afford 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-neopentylacetamide. (40 mg, 0.083 mmol, 59%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[C:15]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]=O)[CH:16]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C1(C2C=CC=CC=2)C=CC=CC=1CN1CCN(C2C=CC=CC=2)CC1>>[C:15]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:12]2[CH2:13][CH2:14][N:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[CH2:10][CH2:11]2)[CH:16]=1
Reactant: COc1ccc(N2CCNCC2)cc1
Reactant: O=Cc1cccc(-c2ccccc2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: c1ccc(-c2ccccc2CN2CCN(c3ccccc3)CC2)cc1
Product: COc1ccc(N2CCN(Cc3cccc(-c4ccccc4)c3)CC2)cc1

Procedure:
128.2 mg of the target compound (0.36 mmol, 65.0%) was obtained using 1-(4-methoxyphenyl)piperazine (212 mg, 1.10 mmol), biphenyl-3-carbaldehyde (100 mg, 0.55 mmol) and NaBH(OAc)3 (355 mg, 1.65 mmol) according to the synthesis method of Compound 1.