Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7](=O)[CH2:8][CH3:9])[S:5][CH:6]=1.O.NN.[OH-].[K+].Cl>C(O)CO.O>[Br:1][C:2]1[CH:3]=[C:4]([CH2:7][CH2:8][CH3:9])[S:5][CH:6]=1
Reactant: CCC(=O)c1cc(Br)cs1
Agent: Cl
Agent: NN
Agent: [K+]
Solvent: O
Solvent: OCCO
Product: CCCc1cc(Br)cs1
Temperature: 160 °C
Reaction time: 0.75 h
Yield: 54 %

Procedure:
To a solution of crude 1-(4-bromo-2-thienyl)-1-propanone, (53 g, 242 mmol, from step 1d above) in 210 mL of ethylene glycol was added hydrazine monohydrate (30 mL, 617 mmol). The resulting solution was then heated to 160° C. with stirring for 45 min. The solution was cooled to 35° C. and 42 g of KOH (750 mmol) was added. The mixture was heated to 160° C. and stirred for 1.5 hr. The reaction was cooled to room temperature, and 450 mL of water was added. The mixture was then acidified with conc. HCl, and the product was extracted with pentane (3×200mL). The pentane was dried over MgSO4, filtered and evaporated to yield 39.7 g of crude product as a free flowing oil. The material was purified by flash chromatography on silica gel, eluting with pentane, to afford 27 g, (54% yield) of the title product. b.p. 120°-125° C. @7 mm Hg. NMR (CDCl3) δ: 0.97 (t, 3H, J=7.5 Hz), 1.69 (sextet, 2H, J=7.5 Hz), 2.75 (t, 2H, J=7.5 Hz), 6.70 (d, 1H), 7.00 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Cl)=[CH:4][CH:3]=1.C(#N)C.[CH2:13]([NH2:16])[CH2:14][CH3:15].[OH-].[Na+]>O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:16][CH2:13][CH2:14][CH3:15])=[CH:4][CH:3]=1
Reactant: CCCN
Reactant: ClCc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: CCCNCc1ccc(Cl)cc1
Reaction time: 0.75 h

Procedure:
A solution of 48.3 g. 4-chlorobenzyl chloride in 40 ml. acetonitrile was added to a mixture of 18 g. propylamine, 12.6 g. sodium hydroxide, 50 ml. acetonitrile and 30 ml. water. The mixture was shaken intermittently for 45 minutes. An exothermic reaction occurred and a white solid separated in the lower phase. After a period of 4 days the reaction mixture was poured into a liter of water and the organic phase isolated with ether. Distillation of the ethereal extract gave an oily product N-4-chlorobenzyl-N-propylamine, b.p. 101°-106° C./1.7-2.5 mm. Hg.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[N:11]=[C:12]4[C:18]([C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:17][N:16]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:13]4=[N:14][CH:15]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Cl.Cl[CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=1.C(=O)(O)[O-].[Na+]>CCOC(C)=O.CN(C=O)C>[CH3:21][C:20]([CH3:23])([CH3:22])[C:19]([C:18]1[C:12]2[C:13](=[N:14][CH:15]=[C:10]([C:6]3[CH:5]=[C:4]4[C:9](=[CH:8][CH:7]=3)[N:1]([CH2:45][C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=3)[CH:2]=[CH:3]4)[N:11]=2)[N:16]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:31])([CH3:30])[CH3:32])[CH:17]=1)=[O:24]
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3ccc4[nH]ccc4c3)nc12
Reactant: ClCc1ccccn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3ccc4c(ccn4Cc4ccccn4)c3)nc12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a DMF (1 mL) solution of 1-[2-(1H-Indol-5-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one (50 mg, 0.11 mmol; prepared as described in Ex. 45, only using the Sem-protected starting material) was added NaHMDS (0.25 mL, 1M in THF) and stirred for 20 min at RT. 2-Chloromethylpyridine hydrochloride (21.6 mg, 0.13 mmol) was added in a single portion. After stirring for 1 hr at RT TLC analysis (25% EtOAc/hexanes) shows a new more-polar product. The reaction mixture was poured into 25 mL of saturated sodium bicarbonate solution and extracted with EtOAc (2×15 mL). The organic layers were combined, washed with brine, dried over MgSO4, and concentrated to give a yellow oil. Chromatography (SiO2; 0%-13%-25% EtOAc in hexanes) gives 2,2-Dimethyl-1-[2-(1-pyridin-2-ylmethyl-1H-indol-5-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-propan-1-one as a clear oil. Following general procedures as described in these Examples, the SEM group was removed to give 2,2-Dimethyl-1-[2-(1-pyridin-2-ylmethyl-1H-indol-5-yl)-5Hpyrrolo[2,3-b]pyrazin-7-yl]propan-1-one (47%; MS=410 [M+H]; MP: 194-196° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[C:6]([C:8]([OH:10])=O)[O:5][N:4]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:44][C@H:45]([CH2:54][C:55]1[CH:60]=[CH:59][C:58]([C:61]2[CH:66]=[CH:65][CH:64]=[C:63]([Cl:67])[CH:62]=2)=[CH:57][CH:56]=1)[CH2:46][C@:47]([CH2:52][OH:53])([CH3:51])[C:48]([OH:50])=[O:49]>CN(C=O)C>[Cl:67][C:63]1[CH:62]=[C:61]([C:58]2[CH:57]=[CH:56][C:55]([CH2:54][C@@H:45]([NH:44][C:8]([C:6]3[O:5][N:4]=[C:3]([O:2][CH3:1])[CH:7]=3)=[O:10])[CH2:46][C@:47]([CH2:52][OH:53])([CH3:51])[C:48]([OH:50])=[O:49])=[CH:60][CH:59]=2)[CH:66]=[CH:65][CH:64]=1
Reactant: C[C@@](CO)(C[C@H](N)Cc1ccc(-c2cccc(Cl)c2)cc1)C(=O)O
Reactant: COc1cc(C(=O)O)on1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C(=O)N[C@H](Cc2ccc(-c3cccc(Cl)c3)cc2)C[C@@](C)(CO)C(=O)O)on1
Reaction time: 0.08 h
Yield: 14.5 %

Procedure:
3-Methoxyisoxazole-5-carboxylic acid (9 mg, 32 μmol) was combined with HATU (12 mg, 32 μmol) and DMF (0.2 mL) and the resulting mixture was stirred for 5 minutes. DIPEA (17 μL, 96 μmol) and (2S,4R)-4-amino-5-(3′-chlorobiphenyl-4-yl)-2-hydroxymethyl-2-methylpentanoic acid (79 mg, 38 μmol) pre-dissolved in DMF were added and the resulting mixture was stirred for 15 minutes then concentrated. The residue was dissolved in AcOH and purified by preparative HPLC to yield the title compound (2.2 mg). MS m/z [M+H]+ calc'd for C24H25ClN2O6, 473.14. found 473.2.
Reaction SMILES: [N:1]1([C:6]2[C:11]([F:12])=[C:10]([NH:13][NH2:14])[N:9]=[C:8]([CH3:15])[N:7]=2)[CH2:5][CH:4]=[CH:3][CH2:2]1.[CH:16]1([CH2:21][C@H:22]([CH2:26][N:27]([CH:35]=[O:36])[O:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][O:30]2)[C:23](O)=[O:24])[CH2:20][CH2:19][CH2:18][CH2:17]1.C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.C(Cl)CCl>CN(C=O)C>[CH:16]1([CH2:21][C@@H:22]([C:23]([NH:14][NH:13][C:10]2[C:11]([F:12])=[C:6]([N:1]3[CH2:2][CH:3]=[CH:4][CH2:5]3)[N:7]=[C:8]([CH3:15])[N:9]=2)=[O:24])[CH2:26][N:27]([O:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][O:30]2)[CH:35]=[O:36])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)O)OC1CCCCO1
Reactant: Cc1nc(NN)c(F)c(N2CC=CC2)n1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: Cc1nc(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OC2CCCCO2)c(F)c(N2CC=CC2)n1
Yield: 42 %

Procedure:
4-(2,5-Dihydro-1H-pyrrol-1-yl)-5-fluoro-6-hydrazino-2-methylpyrimidine (142 mg, 0.68 mmol), (2R)-3-cyclopentyl-2-{[formyl(tetrahydro-2H-pyran-2-yloxy)amino]methyl}propanoic acid (242 mg, 0.81 mmol), and HOAt (110 mg, 0.81 mmol) were dissolved in 4 mL of DMF. NMM (370 μL, 3.4 mmol) was added, followed by EDC (155 mg, 0.81 mmol). When the starting materials were consumed, the reaction mixture was purified by RP-HPLC to provide ((2R)-2-(cyclopentylmethyl)-3-{2-[6-(2,5-dihydro-1H-pyrrol-1-yl)-5-fluoro-2-methyl-4-pyrimidinyl]hydrazino}-3-oxopropyl)(tetrahydro-2H-pyran-2-yloxy)formamide (140 mg, 55%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:13])([CH3:12])[C:7](=[O:14])[C:6]([C:15]([NH:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:16])=[C:5]2[OH:26].[C:27]1(B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[K+].[K+].O>CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[C:27]1([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[C:8]([CH3:13])([CH3:12])[C:7](=[O:14])[C:6]([C:15]([NH:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:23])[CH3:24])=[O:20])=[O:16])=[C:5]3[OH:26])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: OB(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2cc(Br)ccc2C(C)(C)C1=O
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2cc(-c3ccccc3)ccc2C(C)(C)C1=O
Temperature: 110 °C
Yield: 68.5 %

Procedure:
To 1,1-dimethylethyl N-((6-bromo-4-hydroxy-1,1-dimethyl-2-oxo-naphthalen-3-yl)carbonyl)glycinate (250 mg, 658 μmol, Example 40A-D), phenylboronic acid (120 mg, 987 μmol), Pd2(dba)3 (60.3 mg, 65.8 μmol), and X-Phos (62.8 mg, 132 μmol), were added dioxane (3291 μL) and K2CO3 in water (987 μL, 1975 μmol). The reaction was then heated at 110° C. for 6 hours. The resulting reaction mixture was cooled to ambient temperature, diluted with 100 mL of EtOAc, added to a separatory funnel, partitioned with NaHCO3 (saturated, aqueous), washed 2 times with 50 mL of NaHCO3 (saturated, aqueous), separated, dried over Na2SO4, and concentrated in vacuo to give the title compound (190 mg) as an amber amorphous solid after purification via prep-LC. MS (m/z)=444(M+Na)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]3[C:15]([Sn](C)(C)C)=[N:14][N:13]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:10]3=[CH:11][N:12]=2)[CH:2]=1.Br[C:29]1[N:34]=[C:33]([O:35][C@@H:36]2[CH2:41][CH2:40][CH2:39][C@H:38]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46])[CH2:37]2)[CH:32]=[CH:31][CH:30]=1.[F-].[Cs+]>CN(C)C=O.O.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.[Cu]I>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]3[C:15]([C:29]4[N:34]=[C:33]([O:35][C@@H:36]5[CH2:41][CH2:40][CH2:39][C@H:38]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:47])([CH3:46])[CH3:48])[CH2:37]5)[CH:32]=[CH:31][CH:30]=4)=[N:14][N:13]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:10]3=[CH:11][N:12]=2)[CH:2]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H](Oc2cccc(Br)n2)C1
Reactant: C[Si](C)(C)CCOCn1nc([Sn](C)(C)C)c2cc(-c3cccnc3)ncc21
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H](Oc2cccc(-c3nn(COCC[Si](C)(C)C)c4cnc(-c5cccnc5)cc34)n2)C1
Temperature: 50 °C
Yield: 53 %

Procedure:
A mixture of 147 mg (0.3 mmol) of 5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-3-(trimethylstannyl)-1H-pyrazolo[3,4-c]pyridine, 123 mg, 0.33 mmol) of tert-butyl (1S,3R)-3-(6-bromopyridin-2-yloxy)cyclohexylcarbamate, 109 mg (0.72 mmol) of Cesium fluoride, 35 mg (0.03 mmol) of tetrakis(triphenylphosphine)palladium(0) and 11.4 mg (0.06 mmol) of copper(I) iodide in 2 ml of N,N-dimethylformamide was heated at 50° C. for 2 hours in a Stille coupling. The mixture was diluted with water and extracted with ethyl acetate. The organic extracts were washed with water, brine, dried over MgSO4 and concentrated. The residue was purified via silica gel chromatography using a gradient of ethyl acetate in heptane to afford 98 mg (53%) of tert-Butyl (1S,3R)-3-(6-(5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yloxy)cyclohexylcarbamate. ESI MS m/z 617.5 (M+1).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]2[N:9]=[C:10]([N:13]=[C:14]([NH2:16])[NH2:15])[S:11][CH:12]=2)[N:7]=1.[C:17]([O:20][CH2:21][C:22](Cl)=[O:23])(=[O:19])[CH3:18].C(N(CC)CC)C>C(Cl)Cl>[NH2:15][C:14](=[N:13][C:10]1[S:11][CH:12]=[C:8]([C:6]2[N:7]=[C:3]([CH2:2][NH:1][C:22](=[O:23])[CH2:21][O:20][C:17](=[O:19])[CH3:18])[S:4][CH:5]=2)[N:9]=1)[NH2:16]
Reactant: CC(=O)OCC(=O)Cl
Reactant: NCc1nc(-c2csc(N=C(N)N)n2)cs1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OCC(=O)NCc1nc(-c2csc(N=C(N)N)n2)cs1
Yield: 17.1 %

Procedure:
A suspension of 4-(2-aminomethylthiazol-4-yl)-2-(diaminomethyleneamino)thiazole (1.0 g), acetoxyacetyl chloride (0.45 g) and triethylamine (0.93 g) in methylenechloride (30 ml) was stirred with cooling on an ice-water bath for 8 hours. The solvent was removed under reduced pressure. The residue was suspended in water (100 ml). The mixture was neutralized with a saturated aqueous sodium bicarbonate solution and then was extracted with a mixture of ethyl acetate (200 ml) and tetrahydrofuran (60 ml). The extract was dried with magnesium sulfate and then was evaporated. The residue was chromatographed on a silica gel column eluting with chloroform:methanol =10:1. Recrystallization from a mixture of methanol and diisopropyl ether afforded 2-(diaminomethyleneamino)-4-(2-acetoxyacetylaminomethylthiazol-4-yl)thiazole (0.2 g).
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:15][CH:14]=3)=[O:9])=[CH:4][CH:3]=1.[CH3:30][Si]([N-][Si](C)(C)C)(C)C.[Li+].CI>CS(C)=O>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH3:30])[N:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: O=C(NCc1ccc(Cl)cc1)c1nnc2ccc(CN3CCOCC3)cc2c1O
Agent: [Li+]
Solvent: CS(C)=O
Solvent: CI
Product: Cn1nc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)ccc21
Reaction time: 0.25 h
Yield: 39 %

Procedure:
To a suspension of N-(4-chlorobenzyl)-4-hydroxy-6-(4-morpholinylmethyl)-3-cinnolinecarboxamide [Preparation 12] (200 mg) in dry DMSO (15 mL) is added lithium bis(trimethylsilyl)amide (0.51 mL of a 1 M solution in hexanes). The mixture is stirred for 15 min over which time everything dissolves. Methyl iodide (0.032 mL) is then added and the reaction is stirred for an additional 2 h. The mixture is partitioned between EtOAc and water. The aqueous layer is extracted with EtOAc (3×). The combined organic layers are washed with brine, dried and condensed. The crude product is chromatographed on silica (gradient CH2Cl2, 1% MeOH/CH2Cl2, 2% MeOH/CH2Cl2, 3% MeOH/CH2Cl2). Fractions homogeneous by TLC are combined and concentrated. The residue from the column is dissolved in CH2Cl2. Hexanes are added to precipitate the product. The resulting solid is collected and dried to yield 0.079 g (39%) of the title compound as a white solid. Physical characteristics are the same as reported above.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:7])[CH2:5][NH2:6].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CCN(CC)CC.[CH2:36]([C:38]([C:58]1[CH:59]=[C:60]2[C:65](=[CH:66][CH:67]=1)[CH:64]=[C:63]([C:68](O)=[O:69])[CH:62]=[CH:61]2)([C:41]1[CH:46]=[CH:45][C:44]([O:47][CH:48]([CH2:55][CH3:56])[CH:49]([OH:54])[C:50]([CH3:53])([CH3:52])[CH3:51])=[C:43]([CH3:57])[CH:42]=1)[CH2:39][CH3:40])[CH3:37]>C(Cl)Cl>[CH3:2][O:3][C:4](=[O:7])[CH2:5][NH:6][C:68]([C:63]1[CH:62]=[CH:61][C:60]2[C:65](=[CH:66][CH:67]=[C:58]([C:38]([CH2:36][CH3:37])([C:41]3[CH:46]=[CH:45][C:44]([O:47][CH:48]([CH2:55][CH3:56])[CH:49]([OH:54])[C:50]([CH3:51])([CH3:52])[CH3:53])=[C:43]([CH3:57])[CH:42]=3)[CH2:39][CH3:40])[CH:59]=2)[CH:64]=1)=[O:69]
Reactant: COC(=O)CN
Reactant: CCC(Oc1ccc(C(CC)(CC)c2ccc3cc(C(=O)O)ccc3c2)cc1C)C(O)C(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(Oc1ccc(C(CC)(CC)c2ccc3cc(C(=O)NCC(=O)OC)ccc3c2)cc1C)C(O)C(C)(C)C
Yield: 94.6 %

Procedure:
Add glycine methyl ester hydrochloride (95 mg, 0.755 mmol), HOBT (102 mg, 0.755 mmol), EDCI (206 mg, 1.08 mmol), and Et3N (0.4 ml, 0.726 mmol) to diastereomeric isomer pair 1 of 6-{1-ethyl-1-[4-(1-ethyl-2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-naphthalene-2-carboxylic acid (343 mg, 0.72 mmol) and CH2Cl2 (5 ml). Stir the reaction for 14 h. Concentrate the reaction mixture in vacuo, and chromatograph the residue (CH2Cl2 to 15% EtOAc/CH2Cl2) to give the title compound as a colorless foam (373 mg, 95%). 1NMR (400 MHz, CDCl3) δ ppm: 0.64 (t, J=7.6 Hz, 6H), 0.93 (t, J=8.4 Hz, 3H), 0.93 (s, 9H), 1.68 (m, 1H), 1.81 (m, 1H), 2.12 (s, 3H), 2.18 (q, 4H), 2.60 (bs, 1H), 3.27 (s, 1H), 3.83 (s, 3H), 4.27 (dd, J=5.6, 3.2 Hz, 1H), 4.31 (d, J=5.2 Hz, 2H), 6.63 (d, J=8.0 Hz, 1H), 6.75 (t, J=4.8 Hz, 1H), 6.89 (d, J=2.4 Hz, 1H), 6.93 (dd, J=6.4, 2.0 Hz, 1H), 7.18 (dd, J=6.8, 2.0 Hz, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.83 (d, J=2.0, 1H), 7.86 (m, 2H), 8.26 (s, 1H). High Res. ES-MS: 570.3116; calc. for C34H45NO5+Na: 570.3196.
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl>C(O)C.O>[NH:14]([C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: Nc1ccccc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc(Nc2ccccc2)c([N+](=O)[O-])c1
Reaction time: 0.33 h

Procedure:
4-Fluoro-3-nitrobenzoic acid (21.6 mmol) and an aniline (43.2 mmol) in 15 mL of ethanol were stirred at reflux under argon for 5 h resulting in the formation of an orange precipitate. After 12 h the heterogeneous reaction mixture was poured into 50 mL of 1N HCl(aq) and diluted with 100 mL of water. The solution was stirred for 20 min then the precipitate filtered to yield the 4-anilino-3-nitrobenzoic Acid: e.g. 4-{[3-(benzyloxy)phenyl]amino}-3-nitrobenzoic acid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:17][CH2:16][C@@H:15]3[C@H:10]([O:11][CH2:12][CH2:13][NH:14]3)[CH2:9]2)=[CH:6][C:5]([C:18]#[N:19])=[CH:4][C:3]=1[NH:20][C:21]1[N:26]=[C:25]([NH:27][CH2:28][CH3:29])[C:24]2=[N:30][CH:31]=[C:32]([C:33]#[N:34])[N:23]2[N:22]=1.C(OC)(OC)OC.CC(O)=O.[O:46]1[CH2:49][C:48](=O)[CH2:47]1>CO.CCOC(C)=O.C1COCC1>[Cl:1][C:2]1[C:7]([N:8]2[CH2:17][CH2:16][C@@H:15]3[C@H:10]([O:11][CH2:12][CH2:13][N:14]3[CH:48]3[CH2:49][O:46][CH2:47]3)[CH2:9]2)=[CH:6][C:5]([C:18]#[N:19])=[CH:4][C:3]=1[NH:20][C:21]1[N:26]=[C:25]([NH:27][CH2:28][CH3:29])[C:24]2=[N:30][CH:31]=[C:32]([C:33]#[N:34])[N:23]2[N:22]=1
Reactant: CCNc1nc(Nc2cc(C#N)cc(N3CC[C@H]4NCCO[C@@H]4C3)c2Cl)nn2c(C#N)cnc12
Reactant: O=C1COC1
Solvent: C1CCOC1
Solvent: COC(OC)OC
Solvent: CC(=O)O
Product: CCNc1nc(Nc2cc(C#N)cc(N3CC[C@@H]4[C@@H](C3)OCCN4C3COC3)c2Cl)nn2c(C#N)cnc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 21.4 %

Procedure:
(+/−)-2-((2-chloro-5-cyano-3-((4aR,8aR)-hexahydro-1H-pyrido[3,4-b][1,4]oxazin-6(7H)-yl)phenyl)amino)-4-(ethylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Example 371) (10 mg, 0.021 mmol) was taken up in MeOH (0.5 mL) and THF (0.5 mL) and trimethyl orthoformate (0.173 mL, 1.566 mmol), AcOH (4.78 μl, 0.084 mmol), and oxetan-3-one (0.013 mL, 0.209 mmol) were added. The reaction was stirred at 25° C. for 2 hr, then NaCNBH4 (0.209 mL, 0.209 mmol) was added and the reaction stirred at 25° C. overnight. The reaction mixture was diluted with EtOAc and washed with sat'd NaHCO3, then brine. The organic layer was dried over Na2SO4, filtered, and concentrated. The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×200 mm, particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: water with 20-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 20-mM ammonium acetate; Gradient: 45-85% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. The material was further purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×200 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: water with 20-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 20-mM ammonium acetate; Gradient: 40-80% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to afford (+/−)-2-((2-chloro-5-cyano-3-((4aR,8aR)-1-(oxetan-3-yl)hexahydro-1H-pyrido[3,4-b][1,4]oxazin-6(7H)-yl)phenyl)amino)-4-(ethylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (2.4 mg).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:40])[CH2:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH2:37][CH3:38])([C:22]3[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]4([OH:35])[CH2:34][CH2:33][CH2:32][CH2:31]4)=[C:24]([CH3:36])[CH:23]=3)[CH2:20][CH3:21])=[CH:15][C:14]=2[CH3:39])[CH:12]=1.[Cl-].[NH4+]>CO>[CH2:20]([C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:11]2[CH:12]=[C:7]([CH2:6][C:5]([OH:40])=[O:4])[CH:8]=[N:9][CH:10]=2)=[C:14]([CH3:39])[CH:15]=1)([C:22]1[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]2([OH:35])[CH2:31][CH2:32][CH2:33][CH2:34]2)=[C:24]([CH3:36])[CH:23]=1)[CH2:37][CH3:38])[CH3:21]
Reactant: CCC(CC)(c1ccc(/C=C/C2(O)CCCC2)c(C)c1)c1ccc(-c2cncc(CC(=O)OC)c2)c(C)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CCC(CC)(c1ccc(/C=C/C2(O)CCCC2)c(C)c1)c1ccc(-c2cncc(CC(=O)O)c2)c(C)c1
Reaction time: 2 h
Yield: 82.6 %

Procedure:
A 2 N sodium hydroxide aqueous solution (0.24 mL) was added to a solution of {5-[4-(1-ethyl-1-{4-[(E)-2-(1-hydroxy-cyclopentyl)-vinyl]-3-methyl-phenyl}-propyl)-2-methyl-phenyl]-pyridin-3-yl}-acetic acid methyl ester (Example 86-(1); 41.0 mg, 0.08 mmol) in methanol (1.3 mL), and the mixture was stirred for two hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by thin layer silica gel chromatography (10% methanol/dichloromethane) to give the title compound (32.9 mg, 82%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[C:9]([O:13][C:14]([CH:16]([C:28](=[O:30])[CH3:29])[CH:17]([CH:23]([O:26][CH3:27])[O:24][CH3:25])[CH2:18][C:19]([O:21][CH3:22])=[O:20])=[O:15])([CH3:12])([CH3:11])[CH3:10].[C:31](Br)#[C:32][CH2:33][CH2:34][CH3:35]>CC(C)=O>[C:28]([C:16]([C:14]([O:13][C:9]([CH3:11])([CH3:10])[CH3:12])=[O:15])([CH2:31][C:32]#[C:33][CH2:34][CH3:35])[CH:17]([CH:23]([O:24][CH3:25])[O:26][CH3:27])[CH2:18][C:19]([O:21][CH3:22])=[O:20])(=[O:30])[CH3:29]
Reactant: CCCC#CBr
Reactant: COC(=O)CC(C(OC)OC)C(C(C)=O)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCC#CCC(C(C)=O)(C(=O)OC(C)(C)C)C(CC(=O)OC)C(OC)OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 1.38 g quantity of potassium carbonate and 308 mg of potassium iodide are placed into a reactor. Acetone (30 ml) and a solution of 450 mg of methyl 4-tert-butoxycarbonyl-3-dimethoxymethyl-5-oxohexanoate in 10 ml of acetone are further placed into the reactor. Subsequently 270 mg of pentynyl bromide is added to the mixture. The resulting mixture is stirred at room temperature for one hour and thereafter refluxed at 70° C. for 13 hours. On completion of the reaction, the mixture is cooled to room temperature, and the solids are separated off. The product is concentrated in a vacuum, and the residue purified by a silica gel column, giving methyl 4-acetyl-4-tert-butoxycarbonyl-3-dimethoxymethyl-6-nonynoate (compound (6), R1 =t-Bu, R2 =R3 =CH3) in a yield of 91%.