Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[C:9]([C:11](O)=[O:12])[CH:10]=[C:5]2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[NH2:29][CH2:30][CH:31]([OH:33])[CH3:32].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[OH:33][CH:31]([CH3:32])[CH2:30][NH:29][C:11]([C:9]1[CH:10]=[C:5]2[N:4]=[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:26])([F:28])[F:27])[CH:21]=[CH:20][C:18]=4[N:19]=3)[N:2]([CH3:1])[C:6]2=[N:7][CH:8]=1)=[O:12]
Reactant: CC(O)CN
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)cnc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(O)CNC(=O)c1cnc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C
Yield: 65.5 %

Procedure:
3-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-3H-imidazo[4,5-b]pyridine-6-carboxylic acid (2-hydroxy-propyl)-amide (56 mg) was prepared by following General Procedure F starting from 3-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-3H-imidazo[4,5-b]pyridine-6-carboxylic acid (75 mg), 1-amino-2-propanol (15 mg), HBTU (83 mg), and DIEA (48 uL). LC/MS: m/z 466.7. 1H NMR (DMSO-d6, 400 MHz): δ 8.36 (s, 1H), 8.10 (s, 1H), 7.92 (s, 1H), 7.80 (d, 1H), 7.73 (d, 1H), 7.49 (d, 1H), 7.36 (d, 1H), 4.77 (d, 1H), 3.89-3.77 (m, 1H), 3.64 (s, 3H), 3.27-3.16 (m, 2H), 1.10 (d, 3H).
Reaction SMILES: [CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]4[CH:25]=[CH:24][CH:23]=[C:22](O)[CH:21]=4)[N:13]=3)=[CH:4][C:3]=2[O:2]1.ClC1N=C(NC2C=CC3OCCOC=3C=2)C(F)=CN=1.[CH2:46]([O:48][C:49](C1C=C(C=CC=1)N)=[O:50])[CH3:47]>>[CH2:46]([O:48][C:49]([C:22]1[CH:21]=[C:20]([NH:19][C:14]2[N:13]=[C:12]([NH:11][C:5]3[CH:6]=[CH:7][C:8]4[O:9][CH2:10][CH2:1][O:2][C:3]=4[CH:4]=3)[C:17]([F:18])=[CH:16][N:15]=2)[CH:25]=[CH:24][CH:23]=1)=[O:50])[CH3:47]
Reactant: Oc1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1
Reactant: CCOC(=O)c1cccc(N)c1
Agent: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Product: CCOC(=O)c1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1

Procedure:
In like manner to preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and 3-ethoxycarbonylaniline gave N2-(3-ethoxycarbonylphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 8.04 (bs, 1H), 7.94 (bs, 1H), 7.90 (bd, 1H), 7.68 (bd, 1H, J=7.5 Hz), 7.35 (t, 1H, J=8.1 Hz), 7.28 (d, 1H, J=2.4 Hz), 7.07 (s, 1H), 6.93 (dd, 1H, J=3 and 8.7 Hz), 6.83 (d, 1H, J=9 Hz), 6.64 (bs, 1H), 4.36 (q, 2H, J=7.2 Hz), 4.26 9s, 4H), 1.35 (t, 3H, J=7.5 Hz); 19F NMR (CDCl3): −47247; LCMS: ret. time: 15.88; purity: 100%; MS (m/e): 411 (MH+).
Reaction SMILES: [CH:1]1([CH2:6][CH2:7][CH:8]([CH3:13])[CH2:9][CH:10]=[N:11]O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(OC(=O)C)(=O)C>>[CH:1]1([CH2:6][CH2:7][CH:8]([CH3:13])[CH2:9][C:10]#[N:11])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(CC=NO)CCC1CCCC1
Solvent: CC(=O)OC(C)=O
Product: CC(CC#N)CCC1CCCC1
Temperature: 0 °C
Yield: 57.5 %

Procedure:
5-cyclopentyl-3-methylpentanal oxime (3.7 g; 20 mmol) and acetic anhydride (4.5 g; 40 mmol) were heated at 110° C. during 1.5 hours, poured into ice-water (100 ml), and extracted with MTBE (150 ml). The organic phase was washed with brine (4×150 ml), dried (MgSO4), concentrated in vacuo, and purified by flash chromatography (MTBE/hexane 1:15) to give 1.9 g (57% yield) of 5-cyclopentyl-3-methylpentanenitrile.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Br:12][CH2:13][C:14](Br)=[O:15]>CN(C=O)C.O1CCOCC1>[Br:12][CH2:13][C:14]([NH:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])=[O:15]
Reactant: O=C(Br)CBr
Reactant: Nc1c(Cl)cccc1C(=O)O
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: O=C(CBr)Nc1c(Cl)cccc1C(=O)O
Reaction time: 4 h
Yield: 65 %

Procedure:
A solution of 2-amino-3-chlorobenzoic acid (7.0 g, 0.041 mol) in anhydrous DMF (20 mL) and anhydrous dioxane (20 mL) was cooled to 0° C. in a 250 mL 3-necked flask which was fitted with a magnetic stirring bar and a constant additional funnel. Bromoacetyl bromide was added dropwise over a 27 min period while keeping the internal temperature between 0° C. and 2° C. After the addition was complete, the ice-bath was removed and stirring was continued for 4 h. The reaction mixture was cooled using an ice-bath, water (100 mL) was added, and then the yellow precipitate which formed was filtered. The filtered solid was washed with water and then dried in a vacuum oven for 2 days, yielding 7.7 g (65%) of the title compound as a light yellow crystals: mp 173°-175° C.; 1H NMR (CD3OD) δ7.88 (dd, 1H, J=1.6, J=6), 7.68 (dd, 1H, J=1.2, J=6.8), 7.39 (t, 1H, J=8), 6.6 (bs, 1H, NH), 4.06 (s, 2H); 13C NMR (CD3OD) δ176.57, 168.38, 134.84, 134.40, 131.95, 130.53, 129.15, 129.05, 28.66; MS (EI, m/z) 293 (M+).
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.Cl.[NH2:19][CH2:20][C:21](=[O:29])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>ClCCl>[C:23]1([CH2:22][C:21](=[O:29])[CH2:20][NH:19][C:2](=[O:9])[C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: NCC(=O)Cc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(CNC(=O)c1ccncc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.12 h
Yield: 89.7 %

Procedure:
Isonicotinoyl chloride hydrochloride (1.44 g, 8.09 mmol) was stirred in dry dichloromethane (20 ml) and triethylamine (4.0 ml, 2.9 g, 20 mmol) was added. The mixture was stirred at 25° C. for 5-10 minutes, then cooled in an ice bath. 1-Amino-3-phenyl-2-propanone hydrochloride (1.00 g, 5.39 mmol) was added in portions over 4 minutes. The reaction was stirred 0.5 hour while warming to 25° C., then 0.5 hour at 25° C. Water (5-10 ml) was added and the mixture was stirred 5 minutes before being extracted with ethyl acetate (75 ml). The organic layer was washed with saturated aqueous sodium bicabonate (2×35 ml) and saturated aqueous sodium chloride (35 ml), dried (sodium sulfate), decanted, and evaporated. The residue was purified by flash column chromatography on silica gel (50 g) eluted with 5% isopropanol in dichloromethane, yielding N-(3-phenyl-2-oxopropyl)isonicotinamide (1.23 g, 89% yield) as an orange oil which crystallized (m.p. 85°-86° C.) upon standing. Recrystallization of a portion of this material from toluene raised the m.p. to 86°-88° C.
Reaction SMILES: [CH2:1]([P:4]([CH:9]([P:34]([CH2:39][CH:40]=[CH2:41])([CH2:36][CH:37]=[CH2:38])=[O:35])[NH:10][C:11](=[O:33])[NH:12][CH2:13][CH2:14][CH2:15][C:16]([O:18]CC1C2C=CC=CC=2C2C1=CC=CC=2)=[O:17])([CH2:6][CH:7]=[CH2:8])=[O:5])[CH:2]=[CH2:3].N1CCCCC1>CN(C=O)C.C([O-])(O)=O.[Na+]>[CH2:1]([P:4]([CH:9]([P:34]([CH2:36][CH:37]=[CH2:38])([CH2:39][CH:40]=[CH2:41])=[O:35])[NH:10][C:11](=[O:33])[NH:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])([CH2:6][CH:7]=[CH2:8])=[O:5])[CH:2]=[CH2:3]
Reactant: C=CCP(=O)(CC=C)C(NC(=O)NCCCC(=O)OCC1c2ccccc2-c2ccccc21)P(=O)(CC=C)CC=C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: C=CCP(=O)(CC=C)C(NC(=O)NCCCC(=O)O)P(=O)(CC=C)CC=C
Reaction time: 0.83 h
Yield: 105.8 %

Procedure:
Ester 152 (778 mg, 1.18 mmol) was treated with a 5% v/v solution of piperidine in DMF (6 mL). After stirring for 50 min, the reaction mixture was diluted with saturated NaHCO3 solution and washed once with Et2O. The aqueous layer was acidified to pH 2 with conc. HCl solution and extracted with a 4:1 mixture of CHCl3/i-PrOH (3×). The organic layers were combined, dried over MgSO4, filtered and concentrated to dryness, yielding acid 153 as yellowish oil (520 mg, 92%) which was used without purification. 1H NMR (400 MHz, CDCl3) δ 1.84 (quint, J=6.4 Hz, 2H), 2.35 (t, J=6.6 Hz, 2H), 3.26-3.29 (m, 2H), 4.52-4.67 (m, 8H), 5.04 (dt, J=22.2, 10.1 Hz, 1H), 5.20-5.27 (m, 4H), 5.30-5.40 (m, 4H), 5.751 (bs, 1H), 5.84-5.98 (m, 4H), 6.90 (d, J=10.3 Hz, 1H).
Reaction SMILES: O1CCOCC1.[ClH:7].C(OC([N:15]1[CH2:19][CH2:18][CH2:17][C@@H:16]1[CH2:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[CH:31]=1)=O)(C)(C)C>O1CCOCC1>[ClH:7].[CH3:37][O:36][C:32]1[CH:31]=[C:30]([CH2:29][CH2:28][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[O:21][CH2:20][C@H:16]2[CH2:17][CH2:18][CH2:19][NH:15]2)[CH:35]=[CH:34][CH:33]=1
Reactant: COc1cccc(CCc2ccccc2OC[C@H]2CCCN2C(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: C1COCCO1
Product: COc1cccc(CCc2ccccc2OC[C@H]2CCCN2)c1
Reaction time: 1 h

Procedure:
5 ml of a 4N solution of hydrogen chloride dioxane were added to a solution of 540 mg of (R)-1-t-butoxycarbonyl-2-{2-[2-(3-methoxyphenyl)ethyl]phenoxymethyl}pyrrolidine [prepared as described in step (a) above] in 5 ml of dioxane, and the resulting solution was allowed to stand at room temperature for 1 hour. At the end of this time, the solvent was removed by distillation under reduced pressure, and the resulting residue was dried in vacuo, to give 456 mg (a quantitative yield) of the title compound as a colorless oil.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[C:11]([OH:12])=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[O:7].Cl[CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:21]([CH3:26])([CH3:25])[CH2:20][CH2:19][C:18]([CH3:28])([CH3:27])[C:17]=2[CH:16]=1.[Cl-].[NH4+]>CS(C)=O>[CH3:25][C:21]1([CH3:26])[CH2:20][CH2:19][C:18]([CH3:28])([CH3:27])[C:17]2[CH:16]=[C:15]([CH2:14][O:12][C:11]3[CH:10]=[CH:9][CH:8]=[C:5]([CH:6]=[O:7])[C:4]=3[OH:3])[CH:24]=[CH:23][C:22]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(CCl)ccc21
Reactant: O=Cc1cccc(O)c1O
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CS(C)=O
Product: CC1(C)CCC(C)(C)c2cc(COc3cccc(C=O)c3O)ccc21
Reaction time: 1 h

Procedure:
Sodium hydride (2.54 g., 0.106 mol, 2.5 equiv.; 80% dispersion, unwashed) is suspended in 75 mL of DMSO. A solution of 2,3-dihydroxybenzaldehyde (5.84 g., 42.3 mmol, 1 equiv.) in 30 mL of DMSO is added dropwise with water bath cooling, and the mixture allowed to stir 1 hr. at room temperature. A solution of 2-chloromethyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene (18a) (10 g., 42.3 mmol, 1 equiv.) is added and the mixture is allowed to stir overnight at room temperature. The mixture is then poured into half-saturated ammonium chloride solution, and extracted with EtOAc. The aqueous phase is saturated with sodium chloride, and then extracted twice with EtOAc. The combined organic phase is washed with brine, dried (MgSO4), and evaporated. Chromatography on silica gel using 50% CH2Cl2 /hexane affords 3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalenyl)methoxy-salicylaldehyde (19a) as a yellow oil (6.02 g., 17.8 mmol, 44%) which occasionally crystallizes upon standing: UVmax (CHCl3) 268 nm (ε=9894), 240 nm (ε=6181), 350 nm (ε=2513); 1H NMR (300 MHz, CDCl3) δ 11.01 (s, 1H, OH), 9.91 (s, 1H, CHO), 7.33 (d, J=2 Hz, 1H, ArH), 7.29 (d, J=8 Hz, 1H, ArH), 7.21-7.13 (m, 3H, ArH), 6.90 (dd, J=8, 8 Hz, 1H, ArH), 5.10 (s, 2H, ArCH2O), 1.66 (s, 4H, CH2CH2), 1.25 (s, 12H, 4×CH3); 13C NMR (75 MHz, CDCl3) δ 196.45 (C=O), 152.31, 147.46, 145.07, 144.86, 133.33, 126.93, 125.90, 125.12, 125.01, 121.06, 120.97, 119.46, 71.78, 35.03, 35.00, 34.26, 34.16, 31.83; IR (film) 2960, 2926, 2860, 1658, 1456, 1388, 1364, 1276, 1252, 1216, 750, 736 cm-1 ; MS (DCI) m/e 339 (MH+), 201 (C15H21+). Anal. Calcd for C22H26O3.0.4 H2O: C, 76.45; H, 7.81. Found: C, 76.62; H, 7.62.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:10]=[C:11]=S)[CH3:9].[CH3:13][C:14]1[C:15]([NH:29][CH2:30][CH:31]([CH3:33])[CH3:32])=[C:16]([NH2:28])[C:17]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:18][C:19]=1[CH3:20]>N1C=CC=CC=1.C(OCC)(=O)C>[CH2:8]([NH:10][C:11]1[N:29]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:15]2[C:14]([CH3:13])=[C:19]([CH3:20])[N:18]=[C:17]([O:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:16]=2[N:28]=1)[CH3:9]
Reactant: Cc1nc(Oc2ccccc2)c(N)c(NCC(C)C)c1C
Reactant: CCN=C=S
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCNc1nc2c(Oc3ccccc3)nc(C)c(C)c2n1CC(C)C
Temperature: 80 °C
Yield: 58.1 %

Procedure:
Triethylamine (2.44 mL, 17.5 mmol) and ethyl isothiocyanate (0.92 g, 10.5 mmol) were sequentially added to a solution of 5,6-dimethyl-N4-(2-methylpropyl)-2-phenoxypyridine-3,4-diamine (2.5 g, 8.8 mmol) in pyridine (25 mL), and the reaction was heated for five minutes at 80° C. 1,(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.63 g, 10.5 mmol) was added, and the reaction was heated at 100° C. for two hours, allowed to cool to ambient temperature, and diluted with ethyl acetate. The resulting solution was washed sequentially with brine (2×) and saturated aqueous sodium bicarbonate (1×), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide an oil. The crude product was purified by column chromatography on silica gel (eluting with 1-3% methanol in dichloromethane) to provide 1.73 g of N-ethyl-6,7-dimethyl-1-(2-methylpropyl)-4-phenoxy-1H-imidazo[4,5-c]pyridin-2-amine as an oil which solidified to white crystals upon standing overnight at ambient temperature.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[O:22][CH2:23][CH:24]1[CH2:26][CH2:25]1)[C:5]([NH:7][CH:8]1[CH:17]([OH:18])[CH2:16][CH2:15][C:10]2([O:14][CH2:13][CH2:12][O:11]2)[CH2:9]1)=O.C(N(CC)CC)C.O>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[O:18][C:17]3[CH2:16][CH2:15][C:10]4([O:14][CH2:13][CH2:12][O:11]4)[CH2:9][C:8]=3[N:7]=2)[CH:19]=[CH:20][C:21]=1[O:22][CH2:23][CH:24]1[CH2:25][CH2:26]1
Reactant: O=C(NC1CC2(CCC1O)OCCO2)c1ccc(OCC2CC2)c(Cl)c1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: Clc1cc(-c2nc3c(o2)CCC2(C3)OCCO2)ccc1OCC1CC1
Reaction time: 1 h
Yield: 68 %

Procedure:
To a solution of 3-chloro-4-(cyclopropylmethoxy)-N-(8-hydroxy-1,4-dioxaspiro[4.5]dec-7-yl)benzamide (19.4 g) in dimethyl sulfoxide (100 mL) were added triethylamine (22.2 mL) and sulfur trioxide-pyridine complex (25.4 g), and the mixture was stirred for 1 hr under a nitrogen stream. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. To a solution of the obtained residue in THF (100 mL) was added (methoxycarbonylsulfamoyl)triethylammonium hydroxide inner salt (19.0 g), and the mixture was stirred at 60° C. for 1 hr. To the reaction mixture was added saturated brine, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and subjected to silica gel column chromatography (NH, ethyl acetate). The solvent was evaporated, and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (12.5 g).
Reaction SMILES: [CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=[C:3]1[CH:10]=O.[CH3:12][NH:13][C:14](=[O:17])[NH:15][NH2:16].Cl>O.C(O)C>[CH3:12][NH:13][C:14](=[O:17])[NH:15][N:16]=[CH:10][C:3]1[N:2]([CH3:1])[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=1
Reactant: Cn1c([N+](=O)[O-])cnc1C=O
Reactant: CNC(=O)NN
Agent: Cl
Solvent: O
Solvent: CCO
Product: CNC(=O)NN=Cc1ncc([N+](=O)[O-])n1C
Reaction time: 1 h
Yield: 98.1 %

Procedure:
To a solution of 8.5 grams (0.055 mole) of 1-methyl-5-nitro-2-imidazolecarboxaldehyde in 50 ml. of ethanol is added a solution of 5.0 grams (0.056 mole) of 4-methylsemicarbazide in 25 ml. of ethanol and 10 ml. of water containing 2-4 drops of concentrated hydrochloric acid. The resulting solution is heated at 60°-70° C. until a yellow solid starts to separate and then stored at 0° C. for 1 hour; 12.2 grams (98%) of 1-methyl-5-nitro-2-imidazolecarboxaldehyde-4-methylsemicarbazone is obtained melting at 221°-223° C.
Reaction SMILES: [CH2:1]([C:4]1[N:5]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:6]2[C:11]([C:12]=1[CH2:13][C:14](O)=[O:15])=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:2]=[CH2:3].Cl.[NH2:25][C@@H:26]([CH2:31][C:32]1[CH:37]=[C:36]([F:38])[CH:35]=[C:34]([Br:39])[CH:33]=1)[C:27]([O:29][CH3:30])=[O:28].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>C(Cl)Cl>[CH2:1]([C:4]1[N:5]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:6]2[C:11]([C:12]=1[CH2:13][C:14]([NH:25][C@@H:26]([CH2:31][C:32]1[CH:37]=[C:36]([F:38])[CH:35]=[C:34]([Br:39])[CH:33]=1)[C:27]([O:29][CH3:30])=[O:28])=[O:15])=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:2]=[CH2:3]
Reactant: COC(=O)[C@@H](N)Cc1cc(F)cc(Br)c1
Reactant: C=CCc1c(CC(=O)O)c2ccccc2n1C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCc1c(CC(=O)N[C@@H](Cc2cc(F)cc(Br)c2)C(=O)OC)c2ccccc2n1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 65.5 %

Procedure:
2-(2-allyl-1-(tert-butoxycarbonyl)-1H-indol-3-yl)acetic acid (850 mg, 2.7 mmol) and (S)-methyl 2-amino-3-(3-bromo-5-fluorophenyl)propanoate hydrochloride (720 mg, 2.61 mmol) were combined in DCM (13 mL) and treated with HATU (1.49 g, 3.9 mmol) and iPr2NEt (1.13 mL, 6.5 mmol). After stirring for 16 h at room temperature, the reaction was partitioned between DCM and H2O. The organics were separated and dried over sodium sulfate. After removal of solvent, the crude product was purified by silica gel chromatography to provide (S)-tert-butyl 2-allyl-3-(2-(3-(3-bromo-5-fluorophenyl)-1-methoxy-1-oxopropan-2-ylamino)-2-oxoethyl)-1H-indole-1-carboxylate (0.98 g, 63%). MS (m/z) 573 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:13])[C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].[C:14]([O:18][C:19]([N:21]1[CH2:27][CH2:26][CH2:25][C@H:22]1[CH2:23]O)=[O:20])([CH3:17])([CH3:16])[CH3:15].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:14]([O:18][C:19]([N:21]1[CH2:27][CH2:26][CH2:25][CH:22]1[CH2:23][O:12][C:11]1[C:2]([Cl:1])=[CH:3][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:9][C:10]=1[Cl:13])=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: COC(=O)c1cc(Cl)c(O)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(Cl)c(OCC2CCCN2C(=O)OC(C)(C)C)c(Cl)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 90.1 %

Procedure:
To a stirred solution of methyl 3,5-dichloro-4-hydroxybenzoate (600 mg, 2.714 mmol), N-tert-butoxycarbonylprolinol (546 mg, 2.714 mmol), and Ph3P (854 mg, 3.257 mmol) in THF (10 mL) was added dropwise DIAD (0.68 mL, 3.283 mmol) at room temp and the mixture was stirred for 3 days at room temp, and for 18 hr at 70° C. The reaction mixture was concentrated and the residue was chromatographed on silica-gel with n-hexane-EtOAc (6:1, v/v) as eluent to give 988.8 mg (90%) methyl 4-[1-(tert-butoxycarbonyl)-2-pyrrolidinyl]methoxy-3,5-dichlorobenzoate a pale yellowish oil. 1H-NMR (400 MHz, CDCl3) δ1.44 (s, 9H), 1.88-2.15 (br m, 3H), 2.34 (br s, 1H), 3.40-3.44 (m, 2H), 3.92 (s, 3H), 3.92, 4.14 (m, 1H), 4.18 (br s, 2H), 7.98 (s, 2H); MS (FAB) m/z 404 (M++1).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([NH:19][CH2:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[C:9]([NH:11][C:12](=O)[C:13]([CH3:17])([CH3:16])[CH2:14][CH3:15])[CH:10]=1)(=[O:3])[CH3:2]>CC(O)=O>[CH3:16][C:13]([C:12]1[N:19]([CH2:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:8]2[CH:7]=[CH:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:10][C:9]=2[N:11]=1)([CH3:17])[CH2:14][CH3:15]
Reactant: CCC(C)(C)C(=O)Nc1cc(NC(C)=O)ccc1NCC1CCOCC1
Solvent: CC(=O)O
Product: CCC(C)(C)c1nc2cc(NC(C)=O)ccc2n1CC1CCOCC1

Procedure:
Following the same procedure in Example 1, Step F, using N-{5-(acetylamino)-2-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}-2,2-dimethylbutanamide (5.12 g, 14.2 mmol) in AcOH (60 mL). Yield: 2.30 g (47%). 1H NMR (400 MHz, CHLOROFORM-D): δ 0.78 (t, J=7.42 Hz, 3 H), 1.45-1.60 (m, 10 H), 1.86 (q, J=7.42 Hz, 2 H), 2.19 (s, 3 H), 2.22-2.37 (m, 1 H), 3.24-3.38 (m, 2 H), 3.91-4.02 (m, 2 H), 4.17 (d, J=7.42 Hz, 2 H), 7.26 (d, J=8.5 Hz, 1 H), 7.39 (s, 1 H), 7.53 (dd, J=8.69, 2.05 Hz, 1 H), 7.67 (d, J=1.95 Hz, 1 H); MS (ESI) (M+H)+=344.05.
Reaction SMILES: [C:1](O)(=[O:12])[CH2:2][C:3]1[C:4](=[CH:8][CH:9]=[CH:10][CH:11]=1)[C:5](O)=[O:6].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[OH:6][CH2:5][C:4]1[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=1[CH2:2][CH2:1][OH:12]
Reactant: O=C(O)Cc1ccccc1C(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCCc1ccccc1CO
Yield: 98293.7 %

Procedure:
Dissolve homophthalic acid (22.2 g, 0.123 mmol) in tetrahydrofuran (250 mL) and add dropwise at room temperature to a slurry of lithium aluminum hydride (15.5 g, 0.407 mol) in tetrahydrofuran (500 mL). Heat at reflux for 18 hours, cool in an ice bath and carefully add, by dropwise addition, water (16 mL), followed by 50% sodium hydroxide (16 mL). Remove the ice bath, add water slowly with stirring and stir until the gray precipitate turns white and evolution of gas ceases. Filter, wash solids with methylene chloride, dry (MgSO4) and evaporate the solvent in vacuo to give 2-(2-hydroxymethyl-phenyl)-ethanol as a viscous oil (18.4 g, 98%).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[CH:21]1[S:25][CH2:24][CH2:23][S:22]1.[CH2:26](OC=C)C.[BH4-].[Na+]>C(O)C.O.C(OCC)(=O)C>[Cl:18][C:8]1[CH:9]=[C:10]([C:14]([F:17])([F:15])[F:16])[CH:11]=[C:12]([Cl:13])[C:7]=1[N:6]1[C:2]([NH:1][CH3:26])=[C:3]([CH:21]2[S:22][CH2:23][CH2:24][S:25]2)[C:4]([C:19]#[N:20])=[N:5]1
Reactant: C=COCC
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1C1SCCS1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: CNc1c(C2SCCS2)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 100 %

Procedure:
To the solution of 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-(1,3-dithiolan-2-yl)-1H-pyrazole-3-carbonitrile-ethoxyethylene (1:1) (0.30 g, 0.6 mmol) in ethanol (40 mL) at 5 C was added sodium borohydride (74 mg, 1.9 mmol). The resulting mixture was stirred at room temperature for five hrs and then diluted with water and ethyl acetate. The layers were separated and the organic layer was washed with saturated sodium chloride, dried (Na2SO4), concentrated to afford a yellowish oil (0.27 g, 0.6 mmol); 19-F-NMR: −63.704.
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH3:7])=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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.O>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:2]2[O:6][C:5]([CH3:7])=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:3]=2)=[CH:16][CH:15]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: COC(=O)c1cc(Br)oc1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1cc(-c2ccc(OC)cc2)oc1C
Yield: 88.9 %

Procedure:
A mixture of methyl 5-bromo-2-methyl-3-furancarboxylate (2.6 g), 4-methoxy-phenylboronic acid (2.3 g), tetrakis(triphenylphosphine)palladium(0) (0.7 g), 2N aqueous sodium carbonate solution (15 mL) and 1,2-dimethoxyethane (20 mL) was stirred under reflux overnight under an argon atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (0% ethyl acetate/hexane to 15% ethyl acetate/hexane), and crystallized from ethyl acetate/hexane to give the title compound (2.6 g, 88%) as a white solid.