Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[CH2:2]([N:6]1[CH2:11][CH2:10][N:9]([CH:12]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13]([NH:15][NH3+:16])=[O:14])[C:8](=[O:23])[C:7]1=[O:24])[CH2:3][CH2:4][CH3:5].[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH2:35][CH:34]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:33]1[C:44](O)=[O:45])=[O:31])([CH3:28])([CH3:27])[CH3:26].ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>ClCCCl>[CH2:2]([N:6]1[CH2:11][CH2:10][N:9]([CH:12]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:13]([NH:15][NH:16][C:44]([CH:33]2[CH:34]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH2:35][CH2:36][CH2:37][N:32]2[C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:31])=[O:45])=[O:14])[C:8](=[O:23])[C:7]1=[O:24])[CH2:3][CH2:4][CH3:5]
Reactant: CCCCN1CCN(C(C(=O)N[NH3+])c2ccccc2)C(=O)C1=O
Reactant: CC(C)(C)OC(=O)N1CCCC(c2ccccc2)C1C(=O)O
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CCCCN1CCN(C(C(=O)NNC(=O)C2C(c3ccccc3)CCCN2C(=O)OC(C)(C)C)c2ccccc2)C(=O)C1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 11 %

Procedure:
To a solution of 2-[(4-butyl-2,3-dioxopiperazin-1-yl)(phenyl)acetyl]hydrazinium chloride (94.0 mg, 0.27 mmol) in 1,2-dichloroethane (2 ml) were added 1-(tert-butoxycarbonyl)-3-phenylpiperidine-2-carboxylic acid (71.0 mg, 0.23 mmol), 1-hydroxybenzotriazole (44.5 mg, 0.26 mmol), diisopropylethylamine (0.050 ml, 0.27 mmol), and polystyrene bound carbodiimide (353 mg, 0.46 mmol, 1.34 mmol/g). The reaction was allowed to stir gently at room temperature for 24 h. The reaction was filtered, concentrated, and purified via reverse phase HPLC to yield tert-butyl 2-({2-[(4-butyl-2,3-dioxopiperazin-1-yl)(phenyl)acetyl]hydrazino}carbonyl)-3-phenylpiperidine-1-carboxylate (11%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.[C:11](O)(=[O:15])[C:12]([CH3:14])=[CH2:13]>>[C:11]([O:10][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=1)(=[O:15])[C:12]([CH3:14])=[CH2:13]
Reactant: C=C(C)C(=O)O
Reactant: OCCc1ccc(O)cc1
Product: C=C(C)C(=O)OCCc1ccc(O)cc1

Procedure:
2-(p-hydroxyphenyl)ethyl methacrylate was synthesized by carrying out a dehydration reaction between 2-(p-hydroxyphenyl) ethanol and methacrylic acid in the presence of an acidic catalyst. The 2-(p-hydroxyphenyl)ethyl methacrylate thus obtained was dissolved in 2 -methyoxyethanol and subjected to a radical polymerization by use of an azo-based initiator V-601 (manufactured by Wako Pure Chemical Industries, Ltd.). The reaction product was mixed with water and the resulting polymer was precipitated. In this way, a binder polymer [BP-2] was obtained. The weight average molecular weight of the polymer was 56,000 (using polyhydroxystyrene as a standard substance).
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:42]=[CH:41][N:40]([CH3:43])[C:39](=[O:44])[CH:38]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:1][C:2]([CH3:34])([CH3:35])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:37]3[CH:42]=[CH:41][N:40]([CH3:43])[C:39](=[O:44])[CH:38]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: Cn1ccc(Br)cc1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: C[C@@H](c1ccc(-c2ccn(C)c(=O)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Yield: 42.9 %

Procedure:
A mixture of (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one (200 mg, 0.42 mmol), 4-bromo-1-methylpyridin-2(1H)-one (118 mg, 0.63 mmol), Pd(Ph3P)2Cl2 (20 mg), and 2 M aq Cs2CO3 solution (5 mL, 10 mmol) in 1,4-dioxane (20 mL) was stirred and heated to reflux for 2 h. When the reaction was finished, the mixture was washed with water and extracted with EtOAc. The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated to give the crude product, which was purified by preparative TLC to give (S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (83 mg, 43%). LC-MS Method 2 tR=1.16 min, m/z=921.5; 1H NMR (CDCl3) 1.11 (s, 3H), 1.18 (s, 3H), 1.22 (t, 1H), 1.52 (m, 3H), 2.21 (s, 2H), 2.22-2.34 (m, 2H), 2.34-2.46 (m, 1H), 2.85 (m, 1H), 3.57 (s, 3H), 5.59 (m, 1H), 6.33 (d, 1H), 6.68 (s, 1H), 7.01 (d, 2H), 7.29-7.41 (m, 8H); 1H NMR (CD3OD) 0.98 (s, 3H), 1.29 (s, 3H), 1.58 (d, 3H), 2.17 (s, 2H), 2.22 (m, 1H), 2.50 (m, 2H), 3.08 (m, 1H), 3.59 (s, 3H), 5.59 (m, 1H), 6.61 (d, 1H), 6.66 (s, 1H), 7.08 (m, 2H), 7.30-7.40 (5H), 7.42 (d, 2H), 7.70 (d, 1H).
Reaction SMILES: C(OC(N1CCC(N[C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])C1)=O)(C)(C)C.[CH3:31][O:32][C:33](=[O:38])[CH:34]([NH2:37])[CH2:35][OH:36]>>[CH3:31][O:32][C:33](=[O:38])[CH:34]([NH:37][C:14]([C:16]1[S:17][CH:18]=[CH:19][C:20]=1[NH:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]2[NH:28][CH:29]=[CH:30][C:23]=12)=[O:15])[CH2:35][OH:36]
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2sccc2Nc2ccnc3[nH]ccc23)C1
Reactant: COC(=O)C(N)CO
Product: COC(=O)C(CO)NC(=O)c1sccc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-{[3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carbonyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester using 2-amino-3-hydroxy-propionic acid methyl ester instead of 1-BOC-3-aminopyrrolidine. LCMS (ESI) 361 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.60 (1H, br. s.) 10.09 (1H, s) 8.13 (1H, d, J=7.57 Hz) 8.03 (1H, d, J=5.56 Hz) 7.85 (1H, d, J=5.42 Hz) 7.46 (1H, d, J=5.42 Hz) 7.32 (1H, dd, J=3.22, 2.64 Hz) 6.80 (1H, d, J=5.56 Hz) 6.43 (1H, dd, J=3.39, 1.78 Hz) 5.06 (1H, t, J=6.05 Hz) 4.56 (1H, dt, J=7.53, 5.02 Hz) 3.72-3.83 (2H, m) 3.63 (3H, s)
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]1[N:25]([S:26](=[O:31])(=[O:30])[N:27]([CH3:29])[CH3:28])[C:24]([Si](C(C)(C)C)(C)C)=[N:23][CH:22]=1.O>CN(C)C=O>[CH3:28][N:27]([CH3:29])[S:26]([N:25]1[C:21]([CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][N:5]2[C:1](=[O:11])[C:2]3=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]3[C:4]2=[O:6])=[CH:22][N:23]=[CH:24]1)(=[O:30])=[O:31]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CN(C)S(=O)(=O)n1c(CCCCCCCBr)cnc1[Si](C)(C)C(C)(C)C
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)S(=O)(=O)n1cncc1CCCCCCCN1C(=O)c2ccccc2C1=O
Temperature: 100 °C
Yield: 92.9 %

Procedure:
Potassium phthalimide (1.67 g, 9.00 mmol) was added to a solution of the product from step b (2.10 g, 4.50 mmol) in dry N,N-dimethylformamide (10 ml), under an atmosphere of argon. The mixture was stirred and heated at 100° C. for 18 h and allowed to cool to room temperature. Water (75 ml) was added and the mixture extracted with dichloromethane (3×40 ml). The combined extracts were evaporated, the residue dissolved in ethyl acetate (75 ml) and the solution washed five times with brine. The solvent was evaporated and the residue purified by flash column chromatography (silica; ethyl acetate), from which the product was isolated as a yellow oil (1.75 g, 93%).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]Br)=[CH:6][CH:5]=1.[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:24])=[CH:19][CH:18]=1.O>CS(C)=O>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:25]([S:23]([C:20]2[CH:19]=[CH:18][C:17]([CH3:16])=[CH:22][CH:21]=2)=[O:24])[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:6][CH:5]=1
Reactant: CCOC(=O)CS(=O)c1ccc(C)cc1
Reactant: Clc1ccc(CCCCCBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)C(CCCCCc1ccc(Cl)cc1)S(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
First 1.64 g (37.6 mmol) of sodium hydride in 55% mineral oil suspension, and then 9.8 g (37.6 mmol) of 5-(4-chlorophenyl)pentyl bromide, are added to a solution of 8.5 g (37.6 mmol) of ethyl 4-methylphenylsulfinylacetate in 75 ml of dimethylsulfoxide. Then the mixture is stirred at room temperature for another 4 hours. Then it is poured into water, extracted with ether, the extracts are washed with water, dried and concentrated. The concentrate is chromatographed with a mixture of n-heptane and butanone (2:1) on silica gel. Yield: 8.0 g (52% of theory) of ethyl 7-(4-chlorophenyl)-2-[(4-methylphenyl)sulfinyl]heptanoate, a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[CH2:32]([NH2:40])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[CH:20][C:21]([C:22]([NH:40][CH2:32][CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[O:24])=[CH:25][CH:26]=3)=[CH:17][C:9]1=2
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Reactant: NCCc1ccccc1
Product: O=C(NCCc1ccccc1)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with phenethylamine as in General Procedure 10 to give the title compound. LCMS: m/z=550.96 (M+H+); retention time=0.94 minutes.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]([N+:12]([O-])=O)=[N:4][CH:3]=1.[H][H]>C(O)(=O)C.C(=O)([O-])[O-].[Ca+2].[Pd+2].C(=O)([O-])[O-]>[NH2:12][C:5]1[C:6]([C:8]([O:10][CH3:11])=[O:9])=[N:7][C:2]([F:1])=[CH:3][N:4]=1
Reactant: [H][H]
Reactant: COC(=O)c1nc(F)cnc1[N+](=O)[O-]
Agent: [Pd+2]
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CC(=O)O
Product: COC(=O)c1nc(F)cnc1N
Yield: 11.8 %

Procedure:
In 1.0 mL of acetic acid was dissolved 20 mg of methyl 6-fluoro-3-nitro-2-pyrazinecarboxylate. After adding 6 mg of lead-poisoned palladium-calcium carbonate, hydrogen gas was introduced into the mixture at room temperature under a pressure of 1 atmosphere, until the mixture became absorbing no further quantity of hydrogen gas. The insoluble matter was filtered off from the reaction mixture, and the filtrate was concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent: n-hexane:ethyl acetate=5:1] to obtain 2 mg of methyl 3-amino-6-fluoro-2-pyrazinecarboxylate as a light yellow-colored solid product.
Reaction SMILES: C([O:8][C:9]([CH:11]1[CH2:14][CH:13]([CH2:15][OH:16])[N:12]1CC1C=CC=CC=1)=[O:10])C1C=CC=CC=1.O.[H][H]>CO.[OH-].[OH-].[Pd+2]>[OH:16][CH2:15][CH:13]1[NH:12][CH:11]([C:9]([OH:10])=[O:8])[CH2:14]1
Reactant: O=C(OCc1ccccc1)C1CC(CO)N1Cc1ccccc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C1CC(CO)N1

Procedure:
179 mg (0.575 mmol) of N-benzyl-4-(hydroxymethyl)azetidine-2-carboxylic acid benzyl ester and 60 mg of 20% Pd(OH)2 /C (containing 31% of water) in 30 ml of methanol are hydrogenated in a Parr shaker under 4 atm of hydrogen for 3.5 h. The catalyst is filtered off through a double paper filter and washed with methanol, the solution evaporated, and the residue chromatographed on silica gel (isopropanol/water/conc. NH3 14:5:1) to yield, after evaporation and drying i.v., 53.6 mg (71%) of 4-(hydroxymethyl)azetidine-2-carboxylic acid as a colorless solid. 1H NMR (D2O): δ 4.71 (t, 1H, J=9), 4.56 (m, 1H), 3.80 (m, 2H), 2.81 (dt, 1H, J=12 (d), 9.5 (t)), 2.43 (dt, 1H, J=12.5 (d), 8.5 (t)). IR (nujol): 3239, 3146, 2589, 2438, 1620, 1565, 1410, 1327, 1302, 1188, 1099, 1038, 999, 885, 828, 758, 725 cm-1.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][C:6]=1[OH:14])([CH3:4])([CH3:3])[CH3:2].Br[CH2:16][CH2:17][OH:18]>CC#N>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:6]=1[O:14][CH2:16][CH2:17][OH:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc([N+](=O)[O-])cc1O
Reactant: OCCBr
Solvent: CC#N
Product: CC(C)(C)c1ccc(N)cc1OCCO

Procedure:
2-(2-tert-Butyl-5-aminophenoxy)ethanol (C-4) was synthesized following the general scheme above starting from 2-tert-butyl-5-nitrophenol (C-1-a) and 2-bromoethanol. HPLC ret. time 2.08 min, 10-99% CH3CN, 5 min run; ESI-MS 210.3 m/z (MH+).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C:10]2[CH:11]=[N:12][N:13]([CH3:31])[C:14]=2[C@H:15]2[O:21][CH2:20][C@@H:19]([F:22])[C@H:18]([NH:23]C(=O)OC(C)(C)C)[CH2:17][CH2:16]2)=[O:8])[N:6]=1.[F:32][C:33]1[CH:34]=[C:35]([C:49]2([OH:52])[CH2:51][CH2:50]2)[CH:36]=[C:37]([F:48])[C:38]=1B1OC(C)(C)C(C)(C)O1>>[NH2:23][C@H:18]1[C@H:19]([F:22])[CH2:20][O:21][C@H:15]([C:14]2[N:13]([CH3:31])[N:12]=[CH:11][C:10]=2[NH:9][C:7]([C:5]2[N:6]=[C:2]([C:38]3[C:37]([F:48])=[CH:36][C:35]([C:49]4([OH:52])[CH2:50][CH2:51]4)=[CH:34][C:33]=3[F:32])[S:3][CH:4]=2)=[O:8])[CH2:16][CH2:17]1
Reactant: CC1(C)OB(c2c(F)cc(C3(O)CC3)cc2F)OC1(C)C
Reactant: Cn1ncc(NC(=O)c2csc(Br)n2)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Product: Cn1ncc(NC(=O)c2csc(-c3c(F)cc(C4(O)CC4)cc3F)n2)c1[C@@H]1CC[C@@H](N)[C@H](F)CO1

Procedure:
Following the procedure for Example 101 starting from tert-butyl ((3S,4R,7S)-7-(4-(2-bromothiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-3-fluorooxepan-4-yl)carbamate (Intermediate 99), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with 1-(3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropanol (see US2012/225062) gave 225. LCMS (ES+) m/z 508 (M+1).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[C:11]2[C:24]([CH3:25])=[CH:23][S:22][C:12]=2[N:13]=[C:14]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:15]=1>>[N:18]1[CH:19]=[CH:20][CH:21]=[C:16]([C:14]2[N:15]=[C:10]([NH:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:11]3[C:24]([CH3:25])=[CH:23][S:22][C:12]=3[N:13]=2)[CH:17]=1
Reactant: NCc1ccccc1
Reactant: Cc1csc2nc(-c3cccnc3)nc(Cl)c12
Product: Cc1csc2nc(-c3cccnc3)nc(NCc3ccccc3)c12

Procedure:
With the procedure of Example 1, the reaction of benzylamine with 4-chloro-2-(pyridin-3-yl)-5-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-benzylamino-5-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH3:7])=[C:4]([CH:8]=[O:9])[CH:3]=1.[CH3:10][S:11]([C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1)(=[O:13])=[O:12].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>[CH3:7][C:5]1[O:6][C:2]([C:17]2[CH:18]=[CH:19][C:14]([S:11]([CH3:10])(=[O:13])=[O:12])=[CH:15][CH:16]=2)=[CH:3][C:4]=1[CH:8]=[O:9]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: Cc1oc(Br)cc1C=O
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: Cc1oc(-c2ccc(S(C)(=O)=O)cc2)cc1C=O
Reaction time: 8 h
Yield: 62 %

Procedure:
A mixture of 5-bromo-2-methylfuran-3-carbaldehyde (1.5 g), 4-(methanesulfonyl)phenylboronic acid (2.0 g), tetrakis(triphenylphosphine)palladium(0) (0.5 g), 2N aqueous sodium carbonate solution (10 mL) and 1,2-dimethoxyethane (20 mL) was stirred overnight with refluxing 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 (10% ethyl acetate/hexane to 100% ethyl acetate/hexane), and crystallized from ethyl acetate/hexane to give the title compound (1.3 g, 64%) as a yellow crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[NH2:32][CH:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:35][CH2:34]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:30])([F:31])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([NH:32][CH:33]4[C:41]5[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=5)[CH2:35][CH2:34]4)=[O:24])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Reactant: NC1CCc2ccccc21
Product: O=C(NC1CCc2ccccc21)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 1-aminoindan as in General Procedure 10 to give the title compound. LCMS: m/z=562.95 (M+H+); retention time=0.98 minutes.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:19])[C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][C:12]=2[NH2:18])=[CH:5][CH:4]=1.N1C=CC=CC=1.[C:26](OC(=O)C)(=[O:28])[CH3:27]>CN(C)C=O>[C:26]([NH:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]([NH:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[O:19])=[C:12]([NH2:18])[CH:13]=1)(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(NC(=O)c2ccc(N)cc2N)cc1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: COc1ccc(NC(=O)c2ccc(NC(C)=O)cc2N)cc1
Reaction time: 8 h
Yield: 25.3 %

Procedure:
To a stirred solution of N-(4-methoxyphenyl)-2,4-diaminobenzamide (19 g, 73.8 mmol) in N,N-dimethylformamide (250 mL) was added pyridine (6.6 mL, 81 mmol), followed by acetic anhydride (6.6 mL, 70 mmol). After stirring overnight, the solvents were removed in vacuo and the residue was chromatographed over a silica gel (10% tetrahydrofuran/90% chloroform). The appropriate fractions were combined and concentrated in vacuo to give 5.3 g (24%) of the title compound as an off-white solid.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C@@H:9]([O:13][C:14]1[NH:15][C:16]([NH2:25])=[C:17]2[C:21]([N:22]=1)=[N:20][C:19]([O:23][CH3:24])=[N:18]2)[CH2:10][CH2:11][CH3:12].C(=O)([O-])[O-].[K+].[K+].Br[CH2:33][CH2:34][CH:35]1[CH2:40][CH2:39][O:38][C:37]([CH3:42])([CH3:41])[CH2:36]1>CN(C=O)C>[CH3:41][C:37]1([CH3:42])[CH2:36][CH:35]([CH2:34][CH2:33][N:20]2[C:19]([O:23][CH3:24])=[N:18][C:17]3[C:21]2=[N:22][C:14]([O:13][C@H:9]([CH3:8])[CH2:10][CH2:11][CH3:12])=[N:15][C:16]=3[NH2:25])[CH2:40][CH2:39][O:38]1
Reactant: CC1(C)CC(CCBr)CCO1
Reactant: CCC[C@@H](C)Oc1nc2nc(OC)nc-2c(N)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CCC[C@@H](C)Oc1nc(N)c2nc(OC)n(CCC3CCOC(C)(C)C3)c2n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 85.8 %

Procedure:
2-{[(1R)-1-Methylbutyl]oxy}-8-(methyloxy)-1H-purin-6-amine trifluoroacetate (100 mg, 0.274 mmol) was heated with potassium carbonate (37.8 mg, 0.274 mmol) in dry DMF (2 ml) at 60° C. under nitrogen for 1 hour and then cooled to room temperature. 4-(2-Bromoethyl)-2,2-dimethyltetrahydro-2H-pyran (72.6 mg, 0.328 mmol) was added and the reaction mixture heated at 50° C., for 16 hours. LCMS indicated the reaction to be incomplete and more 4-(2-bromoethyl)-2,2-dimethyltetrahydro-2H-pyran (35 mg) was added, and the reaction stirred at 50° C. for a further 5 hours and then partitioned between water (2 ml) and DCM (5 ml). The aqueous layer was further extracted with DCM (2×5 ml). The combined organic layers were combined and dried by passing through a hydrophobic frit and then evaporated to dryness using a nitrogen blowdown unit. The residue was dissolved in methanol (0.6 ml) and purified by mass directed autopreparation. Evaporation of the product containing fractions under a stream of nitrogen in a blowdown apparatus gave the title compound as a white solid (92 mg).
Reaction SMILES: [Cu]C#N.[C:4]([Mg]Cl)([CH3:7])([CH3:6])[CH3:5].Br[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][N:12]=1.O>C1COCC1>[CH3:5][C:4]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][N:12]=1)([CH3:7])[CH3:6]
Reactant: CC(C)(C)[Mg]Cl
Reactant: Brc1ccc(OCc2ccccc2)cn1
Agent: N#C[Cu]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(OCc2ccccc2)cn1
Reaction time: 0.25 h

Procedure:
To a stirred solution of copper (I) cyanide (18.31 g) in dry THF (400 ml) was added, at −78 C, tertbutylmagnesium chloride (1M in THF, 409 ml). The reaction mixture was stirred at this temperature for 15 min before slowly adding a solution of 2-bromo-5-[(phenylmethyl)oxy]pyridine (13.5 g) in THF. This was stirred for 2 h at −78 C before warming to 25-30 C and stirring for a further 20 h. The reaction mixture was poured into water and extracted with ethyl acetate. This was concentrated in vacuo and purified through silica, eluting with 0-2% ethyl acetate in hexane. Appropriate fractions were combined and concentrated in vacuo to yield the title compound, 6.3 g
Reaction SMILES: [Br-:1].[Br-:2].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.[C:34]([C:37]1[CH:42]=[CH:41][C:40]([NH:43][C:44](=[O:46])[CH3:45])=[CH:39][C:38]=1[O:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)(=[O:36])[CH3:35]>C1COCC1>[CH2:48]([O:47][C:38]1[CH:39]=[C:40]([NH:43][C:44](=[O:46])[CH3:45])[CH:41]=[CH:42][C:37]=1[C:34](=[O:36])[CH:35]([Br:2])[Br:1])[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1
Reactant: [Br-]
Reactant: CC(=O)Nc1ccc(C(C)=O)c(OCc2ccccc2)c1
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(C(=O)C(Br)Br)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.7 %

Procedure:
Phenyltrimethylammonium tribromide (102 mg, 0.272 mmol) was added to a solution of N-(4-acetyl-3-benzyloxy-phenyl)-acetamide (35 mg, 0.124 mmol) in THF (3.5 mL), and stirred at room temperature for 2 hours. The mixture was partitioned between water (25 mL) and EtOAc (25 mL), the layers separated and the organic layer dried (MgSO4). The solvents were removed in vacuo to give crude N-[3-benzyloxy-4-(2,2-dibromo-acetyl)-phenyl]-acetamide (54 mg, 100%) as a pale brown solid; δH (CDCl3) 7.92 (1H, br s), 7.85 (1H, d, J=8.5 Hz), 7.55 (1H, br s), 7.50-7.35 (5H, m), 7.09 (1H, s), 6.78 (1H, dd, J=8.5, 1.9 Hz), 5.20 (2H, s), 2.21 (3H, s); LCMS retention time 2.65 min, M+H+ 440.1/442.1/444.1. The mixture was used crude in the next step.