Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH2:15])[CH:6]=[C:7]([O:12][CH3:13])[C:8]=1[CH2:9][CH2:10][CH3:11].Br[C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=1)[C:20]([OH:22])=[O:21].COC1C=C(C=CC2C=CC(C(O)=O)=CC=2)C=C(OC)C=1CCC>>[CH3:13][O:12][C:7]1[CH:6]=[C:5]([CH:14]=[CH:15][C:17]2[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=2)[C:20]([OH:22])=[O:21])[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[CH2:9][CH2:10][CH3:11]
Reactant: C=Cc1cc(OC)c(CCC)c(OC)c1
Reactant: O=C(O)c1cccc(Br)c1
Agent: CCCc1c(OC)cc(C=Cc2ccc(C(=O)O)cc2)cc1OC
Product: CCCc1c(OC)cc(C=Cc2cccc(C(=O)O)c2)cc1OC
Yield: 77 %

Procedure:
This compound was synthesized from (3,5-dimethoxy-4-1-propylphenyl)-ethene and 3-bromobenzoic acid in 77% yield in the same way as described in preparation of 1B. 1HNMR (CDCl3, ppm): δ 1.32 (d, J=7.1 Hz, 6H), 3.63 (qint, J=7.1 Hz, 1H), 3.90 (s, 6H), 6.76 (s, 6H), 7.08 (d, J=17 Hz, 1H), 7.25 (d, J=17 Hz, 1H), 7.50 (t, J=7.7 Hz, 1H), 7.79 (d, J=7.7 Hz, 1H), 8.04 (d, J=7.7 Hz, 1H), 8.31 (s, 1H).
Reaction SMILES: [NH2:1][C@H:2]([C@@H:10]([OH:28])[CH2:11][C@@H:12]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[S:29]1[CH:33]=[CH:32][N:31]=[CH:30]1>CN(C=O)C>[C:24]([O:23][C:21]([NH:20][C@@H:12]([CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH2:11][C@H:10]([OH:28])[C@@H:2]([NH:1][C:21]([O:23][CH2:24][C:33]1[S:29][CH:30]=[N:31][CH:32]=1)=[O:22])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)=[O:22])([CH3:25])([CH3:27])[CH3:26]
Reactant: c1cscn1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@@H](N)Cc1ccccc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1cncs1
Reaction time: 4 h
Yield: 159.3 %

Procedure:
The product of Example 68D (6.0 g, 15.6 mmoles) was dissolved in 60 ml of DMF under nitrogen atmosphere. To this stirred solution at room temperature was added 5-p-nitrophenyloxycarbonyloxymethyl)thiazole (4.67 g, 15.6 mmole) and the resulting solution was stirred for 4 h. The solvent was removed under reduced pressure by rotary evaporation and the residue dissolved in 150 mL EtOAc. This solution was washed with 5×75 mL 1N NaOH solution, 100 mL brine, dried over Na2SO4. The solvent was removed to afford 8.02 g of a slightly yellowish oil. This material was crystallized from 30 mL EtOAc and 40 mL hexane to afford 6.53 g (80%) of the desired product as a white solid. mp 118°-120° C. H 1NMR (CDCl3) δ8.79 (s, 1H), 7.83 (s, 1H), 7.30-7.15 (m, 8H), 7.08 (m, 2H), 5.23 (s, 2H), 5.14 (d, 1H, J=9 Hz), 4.52 (m, 1H), 3.92-3.72 (m, 3H), 3.65 (m, 1H), 2.85 (d-apparent 2H, J=7.5 Hz), 2.72 (d-apparent, 2H, J=7 Hz), 1,61 (m, 2H), 1.38 (s, 9H). CIMS m/z (526) (M+H)+, 543 (M+18)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]2[CH2:20][CH2:19][NH:18][CH2:17][C:16]2=[O:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[Br:22][CH2:23][C:24]1[CH:25]=[CH:26][C:27]([S:30]([N:18]2[CH2:19][CH2:20][N:15]([CH2:14][CH:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]3)[C:16](=[O:21])[CH2:17]2)(=[O:32])=[O:31])=[CH:28][CH:29]=1
Reactant: O=S(=O)(Cl)c1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(CN2CCNCC2=O)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(CN2CCN(S(=O)(=O)c3ccc(CBr)cc3)CC2=O)CC1
Yield: 49 %

Procedure:
To a solution of 1-[1-(tert-butoxycarbonyl)piperidin-4-ylmethyl]-2-piperazinone (500 mg) in ethyl acetate (15 ml) and sodium bicarbonate solution (10 ml) was added at 0° C. 4-(bromomethyl)benzenesulfonyl chloride (453 mg), and the mixture was stirred at room temperature for 30 minutes. The organic layer was separated, washed with brine, dried and concentrated, and the residue was purified with silica gel column chromatography (hexane: ethyl acetate=2:3) to give colorless crystals of 4-[4-(bromomethyl)benzenesulfonyl]-1-[1-(tert-butoxycarbonyl)piperidin-4-ylmethyl]-2-piperazinone (437 mg).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Br:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:22]([CH2:23][C:24]([OH:26])=O)[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[N:15]=2)=[CH:10][CH:9]=1.[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1.C(N(CC)CC)C>CN(C)C=O>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[N:22]([CH2:23][C:24]([NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)=[O:26])[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[N:15]=2)=[CH:12][CH:13]=1
Reactant: Nc1ccccn1
Reactant: O=C(O)Cn1c(-c2ccc(Br)cc2)nc2cccnc21
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Cn1c(-c2ccc(Br)cc2)nc2cccnc21)Nc1ccccn1
Temperature: 25 °C
Yield: 47 %

Procedure:
Under a nitrogen atmosphere, oxalyl chloride (3.4 g, 0.027 mole) was added dropwise (slowly) to a stirred and chilled (10° C.) suspension of 2-(4-bromophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (8.4 g, 0.025 mole) in anhydrous dimethylformamide (50 ml). The reaction mixture was heated at 55°-60° C. for 4 hours, cooled to room temperature, and added dropwise to a stirred and chilled (10° C.) solution of 2-aminopyridine (2.6 g, 0.028 mole) and triethylamine (5.4 g, 0.0053 mole) in anhydrous dimethyl formamide (100 ml). The reaction was stirred at room temperature overnight. Dimethylformamide (100 ml) was distilled off at 100 mm Hg. The residue was cooled, triturated in potassium bicarbonate solution (2×50 ml), and filtered. The filter cake was rinsed with water (2×50 ml) and recrystallized from ethanolisopropyl ether to give 4.8 g (47%) of white solid, mp. 191.5°-195° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]1([S:13]([CH2:16][CH2:17][CH2:18][C:19]2[N:23]([CH2:24][CH2:25][CH2:26][CH3:27])[N:22]=[C:21]([C:28]([OH:30])=O)[CH:20]=2)(=[O:15])=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Cl-].[NH4+:32]>ClCCl.CN(C=O)C>[C:7]1([S:13]([CH2:16][CH2:17][CH2:18][C:19]2[N:23]([CH2:24][CH2:25][CH2:26][CH3:27])[N:22]=[C:21]([C:28]([NH2:32])=[O:30])[CH:20]=2)(=[O:15])=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: [NH4+]
Reactant: CCCCn1nc(C(=O)O)cc1CCCS(=O)(=O)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCn1nc(C(N)=O)cc1CCCS(=O)(=O)c1ccccc1
Reaction time: 2 h

Procedure:
Oxalyl chloride (7.8 mL, 90.0 mmol) was added slowly via syringe to a solution of 5-(3-benzenesulfonylpropyl)-1-butyl-1H-pyrazole-3-carboxylic acid (10.5 g, 30.0 mmol) in 100 mL of dichloromethane containing one drop of DMF. After 2 hours of stirring, saturated ammonium chloride (100 mL) was added to the reaction mixture and the reaction was maintained for 1 hour. The reaction mixture was concentrated under reduced pressure, diluted with dichloromethane and washed with water. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated to afford 10.4 g of 5-(3-benzenesulfonylpropyl)-1-butyl-1H-pyrazole-3-carboxamide.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([O:25][CH3:26])=[CH:11][C:12](Br)=[C:13]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)=[O:16])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cu][C:28]#[N:29].CN1CCCC1=O.N>O.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[C:10]([O:25][CH3:26])=[CH:11][C:12]([C:28]#[N:29])=[C:13]([C:15](=[O:16])[C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#C[Cu]
Reactant: COc1cc(Br)c(C(=O)c2ccc(C)cc2)cc1OCc1ccccc1
Agent: N
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(C#N)c(C(=O)c2ccc(C)cc2)cc1OCc1ccccc1
Temperature: 200 °C
Yield: 112 %

Procedure:
A mixture of (5-benzyloxy-2-bromo-4-methoxyphenyl)-p-tolylmethanone (reference example 10-1) (1.11 g), copper(I)cyanide (967 mg) and 1-methyl-2-pyrrolidinone (2 mL) was irradiated with microwave to heat at 200° C. for 10 min while stirring. Water, a 28% ammonia in water and ethyl acetate were added. The separated organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was triturated with diethyl ether to give the title compound (1.08 g).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([CH:9]([OH:18])[C:10]2[N:11]=[CH:12][N:13]3[CH:17]=[CH:16][S:15][C:14]=23)[CH:6]=[N:7][CH:8]=1.[CH2:19]([Sn:23](Cl)([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:21][CH3:22].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1>[O-2].[O-2].[Mn+4]>[CH3:1][S:2][C:3]1[CH:4]=[C:5]([C:9]([C:10]2[N:11]=[CH:12][N:13]3[CH:17]=[C:16]([Sn:23]([CH2:24][CH2:25][CH2:26][CH3:27])([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:19][CH2:20][CH2:21][CH3:22])[S:15][C:14]=23)=[O:18])[CH:6]=[N:7][CH:8]=1
Reactant: CSc1cncc(C(O)c2ncn3ccsc23)c1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Mn+4]
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(C(=O)c3cncc(SC)c3)c2s1

Procedure:
A ketone compound (408 mg) was prepared in substantially the same manner as in step b) of Synthesis Example 1, except that 430 mg of 7-[(5-methylthiopyridin-3-yl)hydroxymethyl]imidazo[5,1-b]thiazole and 320 mg of manganese dioxide were used as the starting compounds. 7-(5-Methylthiopyridin-3-yl)carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole (179 mg) was prepared in substantially the same manner as in step c) of Synthesis Example 1, except that 138 mg of the ketone compound, 0.300 ml of tri-n-butylstannyl chloride, and 2.25 ml of a 1.0 N lithium bis(trimethylsilyl)amide/THF solution were used as the starting materials.
Reaction SMILES: C([O:3][C:4](=[O:48])[CH:5]([C:10]1[CH:11]=[C:12]([C:38]2[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][CH:39]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][N:19]([CH:22]([C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=3)[CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[CH2:18][CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])C.[OH-].[Na+]>CO>[CH3:8][CH:7]([CH3:9])[CH2:6][CH:5]([C:10]1[CH:11]=[C:12]([C:38]2[CH:39]=[CH:40][C:41]([C:44]([F:46])([F:47])[F:45])=[CH:42][CH:43]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][N:19]([CH:22]([C:28]3[CH:29]=[CH:30][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:32][CH:33]=3)[CH2:23][CH2:24][CH:25]([CH3:26])[CH3:27])[CH2:18][CH2:17]2)[CH:15]=1)[C:4]([OH:48])=[O:3]
Reactant: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCN(C(CCC(C)C)c3ccc(C(F)(F)F)cc3)CC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)CCC(c1ccc(C(F)(F)F)cc1)N1CCC(c2cc(-c3ccc(C(F)(F)F)cc3)cc(C(CC(C)C)C(=O)O)c2)CC1
Temperature: 50 °C

Procedure:
To a solution of a mixture of 4-methyl-2-(5-{1-[4-methyl-1-(4-trifluoromethyl-phenyl)-pentyl]-piperidin-4-yl}-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester and methyl ester (56 mg, 0.09 mmol) in MeOH (1 mL) was added 3N NaOH (0.060 mL) and heated to 50° C. for 2 h. The reaction was concentrated in vacuo to remove MeOH. The thick liquid was acidified to pH=2 by 2N HCl. The resulting acidic solution was extracted with EtOAc. The organic fraction was dried (MgSO4) and concentrated in vacuo. The crude mixture was purified by ISCO column chromatography to obtain 4-methyl-2-(5-{1-[4-methyl-1-(4-trifluoromethyl-phenyl)-pentyl]-piperidin-4-yl}-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[CH3:14].I[CH2:22][C@H:23]([CH3:30])[CH2:24][CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28]>C1COCC1.CCCCC.CN(P(N(C)C)(N(C)C)=O)C>[C:17]([O:16][C:13](=[O:15])[CH2:14][CH2:22][C@H:23]([CH3:30])[CH2:24][CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(=O)OC(C)(C)C
Reactant: CC(C)CCC[C@@H](C)CI
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC(C)CCC[C@@H](C)CCC(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 87.4 %

Procedure:
To diisopropyl amine (0.827 mL, 5.9 mmol) in THF (8 mL) at −78° C. was added nBuLi (2.65 mL of a 2.6 M solution in pentane). The solution was stirred for 30 min at −78° C., followed by the addition of t-butyl acetate (0.8 mL, 5.9 mmol). The mixture was stirred at −78° C. for 2 h, and then (R)-1-iodo-2,6-dimethyl heptane (0.3 g, 1.18 mmol) and HMPA (1.5 mL) in THF (1 mL) was added. The reaction was stirred at −78° C. and allowed to slowly reach ambient temperature overnight, then heated at 35° C. to drive the reaction to completion. The reaction was quenched by the addition of ammonium chloride (saturated aqueous solution), and the mixture was extracted with EtOAc (2×10 mL). The organics were combined, washed with water, dried (MgSO4), filtered and concentrated. Silica gel chromatography (98/2 hexane/EtOAc) provided 0.25 g of (4R)-4,8-dimethyl nonanoic acid t-butyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([N:14]3[CH:19]([CH3:20])[CH2:18][O:17][CH2:16][CH:15]3[CH3:21])[N:11]=[C:10]([C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][CH3:32])=[O:30])=[CH:24][CH:23]=3)[N:9]=2)=[CH:4][CH:3]=1.[C:33]([C:36]1[CH:41]=[CH:40][C:39]([NH:42][C:43](=O)[O:44]C2C=CC=CC=2)=[CH:38][CH:37]=1)(=[O:35])[NH2:34]>>[CH3:21][CH:15]1[CH2:16][O:17][CH2:18][CH:19]([CH3:20])[N:14]1[C:12]1[N:11]=[C:10]([C:22]2[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:30])[NH:31][CH3:32])=[CH:24][CH:23]=2)[N:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:43]([NH:42][C:39]3[CH:40]=[CH:41][C:36]([C:33]([NH2:34])=[O:35])=[CH:37][CH:38]=3)=[O:44])=[CH:7][CH:6]=2)[N:13]=1
Reactant: CNC(=O)Nc1ccc(-c2nc(-c3ccc(N)cc3)nc(N3C(C)COCC3C)n2)cc1
Reactant: NC(=O)c1ccc(NC(=O)Oc2ccccc2)cc1
Product: CNC(=O)Nc1ccc(-c2nc(-c3ccc(NC(=O)Nc4ccc(C(N)=O)cc4)cc3)nc(N3C(C)COCC3C)n2)cc1
Yield: 12.8 %

Procedure:
The title compound was prepared by following the procedure of example 462 step 7 using 1-(4-(4-(4-aminophenyl)-6-(3,5-dimethylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-methylurea and phenyl 4-carbamoylphenylcarbamate. Yield 70 mg, 12.8% yield.
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][C:7]([N+:12]([O-])=O)=[CH:8][CH:9]=2)[CH2:4][NH:3]1>CO>[CH3:1][CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][C:7]([NH2:12])=[CH:8][CH:9]=2)[CH2:4][NH:3]1
Reactant: CC1Cc2ccc([N+](=O)[O-])cc2CN1
Solvent: CO
Product: CC1Cc2ccc(N)cc2CN1

Procedure:
3-Methyl-7-nitro-1,2,3,4-tetrahydroisoquinoline (3.0 g, 13.1 mmol) was dissolved in MeOH (100 ml) and hydrogenated at 50 psi in the presence of a catalytic quantity of 10% Pd--C. After 1 h the mixture was filtered through glass and evaporated to an oil which was used immediately in the next reaction.
Reaction SMILES: [BH4-].[Na+].C(O)C.[Cl-].[Ca+2].[Cl-].[CH3:9][O:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[C:24]([N:26]([CH2:44][CH:45]([CH3:47])[CH3:46])[C@@H:27]1[CH2:32][N:31]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:30][C@H:29]([C:40](OC)=[O:41])[CH2:28]1)=[O:25]>C1COCC1.O.C(OCC)(=O)C>[OH:41][CH2:40][C@@H:29]1[CH2:28][C@H:27]([N:26]([C:24]([C:16]2[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][O:10][CH3:9])[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[N:17]=2)=[O:25])[CH2:44][CH:45]([CH3:47])[CH3:46])[CH2:32][N:31]([C:33]([O:35][C:36]([CH3:38])([CH3:37])[CH3:39])=[O:34])[CH2:30]1
Reactant: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)OC)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Agent: [BH4-]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](CO)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 47.4 %

Procedure:
Sodium borohydride (4.45 g) was suspended in THF (25 ml)-ethanol (75 ml), and calcium chloride (6.5 g) was added. After stirring at 0° C. for 1 hr, a solution of 1-tert-butyl 3-methyl (3R,5S)-5-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1,3-dicarboxylate (4.0 g) in THF (50 ml) was added. After stirring at room temperature for 12 hr, ethyl acetate (150 ml) and water (50 ml) were slowly added in this order, and the mixture was filtered. The organic layer of the filtrate was partitioned, washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was dried under reduced pressure to give the object product (1.8 g).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([O:8][C@@H:9]2[CH:14]3[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]3)[CH2:10]2)=[CH:4][CH:3]=1.[C:17]([O:21][C:22](=[O:42])[NH:23][C:24]1[CH:29]=[CH:28][C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][C:25]=1[N+:39]([O-:41])=[O:40])([CH3:20])([CH3:19])[CH3:18].[F-].[Cs+]>O1CCOCC1.CN(C=O)C.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]>[C:17]([O:21][C:22](=[O:42])[NH:23][C:24]1[CH:29]=[CH:28][C:27]([C:2]2[N:7]=[N:6][C:5]([O:8][C@@H:9]3[CH:14]4[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]4)[CH2:10]3)=[CH:4][CH:3]=2)=[CH:26][C:25]=1[N+:39]([O-:41])=[O:40])([CH3:20])([CH3:18])[CH3:19]
Reactant: Clc1ccc(O[C@H]2CN3CCC2CC3)nn1
Reactant: CC(C)(C)OC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(O[C@H]3CN4CCC3CC4)nn2)cc1[N+](=O)[O-]

Procedure:
The product of Example 9A (240 mg, 1 mmol) was coupled with the product of Example 28B (0.72, 2 mmol) under the catalysis of Pd2(dba)3 (24 mg, 0.025 mmol) and (tBu3P)2Pd (26 mg, 0.05 mmol) with CsF (Strem Chemicals, 228 mg, 1.5 mmol) in dioxane (8 mL) and DMF (Aldrich, 1 mL) at 80° C. under N2 for 16 hours according to the procedure of Example 20B. The title compound was purified by chromatography (SiO2, EtOAc:MeOH (v. 2% NH3.H2O), 50:50, Rf. 0.3) as yellow solid (350 mg, 79%). 1H NMR (300 MHz, MeOH-D4) δ 1.40 (s, 9H), 1.51-1.70 (m, 1H), 1.70-1.98 (m, 2H), 2.00-2.23 (m, 1H), 2.37-2.51 (m, 1H), 2.71-3.18 (m, 5H), 3.47-3.69 (m, 1H), 5.33-5.49 (m, 1H), 7.30 (d, J=9.2 Hz, 1H), 7.54 (d, J=8.5 Hz, 1H), 7.62 (s, 1H), 8.14 (d, J=9.5 Hz, 1H), 8.37 (dd, J=8.1, 2.0 Hz, 1H), 8.80 (d, J=2.0 Hz, 1H) ppm. MS (DCI/NH3): 442 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][CH2:8][CH2:9][C:10](Cl)=[O:11])=[CH:4][CH:3]=1.[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[Br:1][C:2]1[CH:14]=[CH:13][C:5]2[O:6][CH2:7][CH2:8][CH2:9][C:10](=[O:11])[C:4]=2[CH:3]=1
Reactant: O=C(Cl)CCCOc1ccc(Br)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C1CCCOc2ccc(Br)cc21
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 103.7 %

Procedure:
A solution of 4-(4-bromophenoxy)butanoyl chloride (27.6 g, 100 mmol) in DCM (200 mL) was added dropwise to a solution of AlCl3 (50 g, 0.38 mol) in DCM (100 mL) at 0° C. within 40 minutes, the mixture was stirred at 0° C. for 1.5 hours, and then stirred at room temperature overnight. the mixture was added to a stirred mixture of concentrated hydrochloric (500 mL) and ice, and then stirred for 1.5 hours. The mixture was extracted with DCM, washed with NaHCO3, dried over Na2SO4 and concentrated to give crude 7-bromo-3,4-dihydrobenz o[b]oxepin-5(2H)-one (25 g, 96%).
Reaction SMILES: [NH2:1][CH:2]([C:6]([NH2:8])=[O:7])[C:3]([NH2:5])=[O:4].O.[C:10]1(C)C=CC(S(O)(=O)=[O:17])=CC=1.C(OCC)(OCC)OCC.[ClH:31]>O.CC(O)C>[OH2:4].[OH2:17].[ClH:31].[OH:4][C:3]1[NH:5][CH:10]=[N:1][C:2]=1[C:6]([NH2:8])=[O:7]
Reactant: NC(=O)C(N)C(N)=O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CC(C)O
Solvent: CCOC(OCC)OCC
Solvent: O
Product: NC(=O)c1nc[nH]c1O
Temperature: 82 °C
Reaction time: 3 h

Procedure:
Under the nitrogen atmosphere, 10.0 g of 2-aminomalonamide and 81.2 mg of p-toluene sulfonic acid monohydrate were added to 200 mL of 2-propanol. After heating to 82° C., 35.4 mL of triethyl orthoformate was added dropwise to the mixture over 5 minutes. Subsequently, the reaction mixture was stirred for 3 hours at 80° C. Color of the reaction liquid was deep blue when the reaction was completed. Subsequently, after cooling to 57° C., the reaction mixture was added with 10 mL of water followed by 8 mL of conc. hydrochloric acid. After cooling the reaction mixture to 5° C., the crystal was collected by filtration and then washed with 40 mL of acetone to give 15.6 g of 5-hydroxy-1H-imidazole-4-carboxamide hydrochloric acid salt dihydrate as a green crystal.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[N:3]=1.[N:12]([S:15]([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[N:26]=[N:27][S:28][CH:29]=1)(=[O:17])=[O:16])=[C:13]=[O:14]>O1CCCC1>[CH3:9][O:8][C:6]1[CH:5]=[C:4]([O:10][CH3:11])[N:3]=[C:2]([NH:1][C:13]([NH:12][S:15](=[O:17])(=[O:16])[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]2[N:26]=[N:27][S:28][CH:29]=2)=[O:14])[N:7]=1
Reactant: O=C=NS(=O)(=O)Oc1ccccc1-c1csnn1
Reactant: COc1cc(OC)nc(N)n1
Solvent: C1CCOC1
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)Oc2ccccc2-c2csnn2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 26.7 %

Procedure:
By the procedure of Example 4, 5.3 g of 2-amino-4,6-dimethoxypyrimidine in 20 ml of tetrahydrofuran was reacted with 14 g of the isocyanate prepared in Example 5 above in 30 ml of tetrahydrofuran. After stirring the mixture at 25° C. for 3 hours, the mixture was filtered and the solid isolated was recrystallized from acetonitrile to yield 4 g of the title compound; m.p. 173°-175° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:4]([NH2:17])[C:3]=1[NH2:18].Br[C:20]1[N:25]=[C:24]2[N:26]([CH2:31][CH:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[C:27](=[O:30])[CH2:28][NH:29][C:23]2=[N:22][CH:21]=1.ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(O)(C)C.O1CCOCC1>[NH2:17][C:4]1[CH:5]=[C:6]([C:20]2[N:25]=[C:24]3[N:26]([CH2:31][CH:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)[C:27](=[O:30])[CH2:28][NH:29][C:23]3=[N:22][CH:21]=2)[CH:7]=[C:2]([CH3:1])[C:3]=1[NH2:18]
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(N)c1N
Reactant: O=C1CNc2ncc(Br)nc2N1CC1CCOCC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CC(C)O
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1cc(-c2cnc3c(n2)N(CC2CCOCC2)C(=O)CN3)cc(N)c1N
Temperature: 100 °C
Yield: 99.1 %

Procedure:
3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene-1,2-diamine (0.523 g, 2.109 mmol), 7-bromo-1-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one (0.600 g, 1.834 mmol), [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (0.150 g, 0.183 mmol), sodium carbonate (1 M in water, 5.50 mmol), 1,4-dioxane (4.1 mL) and isopropanol (1.4 mL) were combined in a sealable vessel with a stirbar. The system was purged with nitrogen. The resulting mixture was sealed, stirred vigorously and heated at 100° C. for 3.5 h. The resulting mixture was diluted with 20% methanol in dichloromethane and all volatiles removed under reduced pressure. The residue was taken up in 20% methanol in dichloromethane and concentrated under reduced pressure with silica gel. The residue was purified using flash chromatography (1-10% methanol in dichloromethane) to give the desired product (0.669 g, 1.818 mmol, 99% yield) as a brown solid. MS (ESI) m/z 369.1 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[C:12]([O:13][CH2:14][C:15]([NH2:17])=[O:16])=[C:11]([Br:18])[CH:10]=[CH:9][C:3]=1[C:4]([O:6]CC)=[O:5].[OH-].[Na+]>C1COCC1.O>[Br:1][C:2]1[C:12]([O:13][CH2:14][C:15]([NH2:17])=[O:16])=[C:11]([Br:18])[CH:10]=[CH:9][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)c1ccc(Br)c(OCC(N)=O)c1Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)COc1c(Br)ccc(C(=O)O)c1Br
Temperature: 25 °C
Reaction time: 12 h

Procedure:
0.700 g (1.80 mmol) of ethyl 2,4-dibromo-3-(aminocarbonylmethoxy)benzoate was dissolved in 15 ml of THF and 15 ml of water, and 0.147 g (3.70 mmol) of NaOH was added. The mixture was stirred for 12 hours at RT and concentrated completely. The residue was taken up in water and 6 N HCl was added. The precipitate which had formed was filtered off with suction and dried. 2,4-dibromo-3-(aminocarbonyl-methoxy)benzoic acid was obtained as a white solid.