Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[S:13][C:12]3[CH:14]=[CH:15][C:16]4[C:21]([C:11]=3[NH:10][CH2:9]2)=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:4][CH:3]=1.C(=O)([O-])O.[Na+].O.[C:28](Cl)(=[O:31])[CH:29]=[CH2:30]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[S:13][C:12]3[CH:14]=[CH:15][C:16]4[C:21]([C:11]=3[N:10]([C:28](=[O:31])[CH:29]=[CH2:30])[CH2:9]2)=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:6][CH:7]=1
Reactant: C=CC(=O)Cl
Reactant: Clc1ccc(C2CNc3c(ccc4ccccc34)S2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: C=CC(=O)N1CC(c2ccc(Cl)cc2)Sc2ccc3ccccc3c21
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.8 %

Procedure:
To a mixture of 3-(4-chlorophenyl)-2,3-dihydro-1H-naphtho[2,1-b][1,4]thiazine (1.50 g), sodium hydrogen carbonate (1.0 g), methylene chloride (30 ml) and water (15 ml) is added dropwise with stirring a solution of acryloyl chloride (0.90 g) in methylene chloride (10 ml) under ice cooling. The mixture is stirred at room temperature for 3 hours. The organic layer is separated, washed, dried and distilled to remove the solvent. The residue is chromatographed on silica gel (toluene: acetone =50 : 1) to give 3-(4-chlorophenyl)-1-propenoyl-2,3-dihydro-1H-naphtho[2,1-b][1,4]thiazine (1.37 g, 78%) as powder.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=3)[O:10][C:3]=12.[C:23]([NH:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH3:22][O:21][C:13]1[CH:12]=[C:11]([C:9]2[O:10][C:3]3[C:4](=[N:5][CH:6]=[CH:7][C:2]=3[C:35]3[CH:34]=[CH:33][C:32]([NH:31][C:23](=[O:30])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:37][CH:36]=3)[CH:8]=2)[CH:16]=[C:15]([O:17][CH3:18])[C:14]=1[O:19][CH3:20]
Reactant: O=C(Nc1ccc(B(O)O)cc1)c1ccccc1
Reactant: COc1cc(-c2cc3nccc(Cl)c3o2)cc(OC)c1OC
Product: COc1cc(-c2cc3nccc(-c4ccc(NC(=O)c5ccccc5)cc4)c3o2)cc(OC)c1OC

Procedure:
The title compound was prepared by procedure C using 7-chloro-2-(3,4,5-trimethoxyphenyl)furo[3,2-b]pyridine (45.00 mg; 0.14 mmol; 1.00 eq.) instead of 7-chloro-2-iodo-furo[3,2-b]pyridine, and 4-benzamidophenylboronic acid (37.32 mg; 0.15 mmol; 1.10 eq.) instead of 4-fluorophenylboronic acid and was obtained as a pale yellow solid (55 mg, 81%). (HPLC (method F): 94%, RT: 4.14 min); MS (m/z) 481 [M+H]+, RT: 4.1 min.
Reaction SMILES: [C:1](Cl)(=O)C.[CH3:5][O:6][C:7]1[C:12]2=[CH:13][CH:14]=[C:15]3[C:24]([N:23]=[C:22]4[C:17]([CH:18]=[CH:19][CH:20]=[C:21]4[C:25]([OH:27])=[O:26])=[N:16]3)=[C:11]2[CH:10]=[CH:9][CH:8]=1>CO>[CH3:1][O:26][C:25]([C:21]1[C:22]2[C:17](=[N:16][C:15]3[C:24]([N:23]=2)=[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([O:6][CH3:5])[C:12]2=[CH:13][CH:14]=3)[CH:18]=[CH:19][CH:20]=1)=[O:27]
Reactant: COc1cccc2c1ccc1nc3cccc(C(=O)O)c3nc12
Reactant: CC(=O)Cl
Solvent: CO
Product: COC(=O)c1cccc2nc3ccc4c(OC)cccc4c3nc12

Procedure:
Acetyl chloride (4.6 mL) was added dropwise to a suspension of 4-methoxy-benzo[a]phenazine-11-carboxylic acid (II.1, see Reference Example 1A, 4.9 g) in methanol (50 mL). The mixture was heated to reflux for 4 hours. The volatiles were then removed in vacuo to yield the title compound as a dark solid (quantitative yield).
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:15])=[C:4]([Cl:14])[C:5]([Cl:13])=[C:6]2[C:11](=[O:12])[O:10][C:8](=[O:9])[C:7]=12.[CH2:16]([N:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[C:25]1[CH3:33])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].[Cl-].[Al+3].[Cl-].[Cl-]>>[CH2:16]([N:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([C:11]([C:6]2[C:5]([Cl:13])=[C:4]([Cl:14])[C:3]([Cl:15])=[C:2]([Cl:1])[C:7]=2[C:8]([OH:10])=[O:9])=[O:12])=[C:25]1[CH3:33])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: O=C1OC(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c21
Reactant: CCCCCCCCn1c(C)cc2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Product: CCCCCCCCn1c(C)c(C(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c2C(=O)O)c2ccccc21

Procedure:
Proceeding in the same manner as that described in part A of Example 6 above, 14.3 g (0.05 mole) of tetrachlorophthalic anhydride, 16.0 g (0.052 mole) of 76.5 percent active 1-n-octyl-2-methylindole and 13.3 g (0.10 mole) of aluminum chloride were interacted to obtain 2-[(1-n-octyl-2-methyl-3-indolyl)carbonyl]-3,4,5,6-tetrachlorobenzoic acid (Formula VIII: R0 =R1 =R2 =R3 =Cl; R5 =CH3 ; R6 =(CH2)7CH3 ; Y1 =H), a pale orange solid melting at 132°-134° C. The infrared spectrum, showing a maximum at 1745 cm-1 (C=O; s) and the nuclear magnetic resonance spectrum was in accord with the structure.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[C:7]([O:24][CH3:25])=[CH:8][C:9]([CH:21]([CH3:23])[CH3:22])=[C:10]([CH:20]=1)[O:11][C:12]1[CH:13]([NH2:19])[NH:14][C:15]([NH2:18])=[N:16][CH:17]=1.I[CH3:27].[OH-].[K+]>CC(C)=O>[CH:21]([C:9]1[CH:8]=[C:7]([O:24][CH3:25])[C:6]([C:2]2[N:1]([CH3:27])[CH:5]=[CH:4][N:3]=2)=[CH:20][C:10]=1[O:11][C:12]1[CH:13]([NH2:19])[NH:14][C:15]([NH2:18])=[N:16][CH:17]=1)([CH3:23])[CH3:22]
Reactant: CI
Reactant: COc1cc(C(C)C)c(OC2=CN=C(N)NC2N)cc1-c1ncc[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Product: COc1cc(C(C)C)c(OC2=CN=C(N)NC2N)cc1-c1nccn1C
Temperature: 30 °C
Yield: 52.2 %

Procedure:
To a solution of 5-[5-(1H-Imidazol-2-yl)-2-isopropyl-4-methoxy-phenoxy]-3,4-dihydro-pyrimidine-2,4-diamine (0.044 g, 0.129 mmols) and iodomethane (9 ul, 0.145 mmols) in acetone (5 ml) was added KOH (0.055 g, 0.98 mmols), the mixture was heated at 30° C. for 20 minutes, the mixture was filtered through celite, washed with CH2Cl2, the combined organic solution was concentrated in vacuo. The residue was purified via preparative TLC silica plates, eluted with 5% MeOH/CH2Cl2/NH4OH four times to give 5-[2-Isopropyl-4-methoxy-5-(1-methyl-1H-imidazol-2-yl)-phenoxy]-3,4-dihydro-pyrimidine-2,4-diamine (0.024 g, 52%). Mass Spec: M+H: 355.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])[NH:11][CH:12]=1.[CH3:18][O-:19].[Na+].CO>>[CH3:18][O:19][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])[NH:11][CH:12]=1
Reactant: C[O-]
Reactant: NCCCCc1nc(-c2cnccc2Cl)c[nH]1
Agent: [Na+]
Solvent: CO
Product: COc1ccncc1-c1c[nH]c(CCCCN)n1
Temperature: 70 °C
Yield: 96 %

Procedure:
To a solution of 4-[4-(4-chloro-3-pyridyl)imidazolyl]butylamine (400 mg, mmoles) was added sodium methoxide, 5.3 M in methanol (10 ml, 53 mmoles). The reaction mixture was heated at 70° C. for 2 hours. Upon cooling the reaction mixture was concentrated to around 4 ml and then was taken up in dichloromethane (125 ml) and was washed with water (20 ml). The aqueous layer was extracted further with dichloromethane (125 ml), the combined organics were dried over MgSO4, filtered, and concentrated yielding 4-[4-(4-methoxy-3-pyridyl)imidazolyl]butylamine (379 mg, 96%). MH+(247).
Reaction SMILES: [I:1][C:2]1[NH:6]C(C(C)C)=[N:4][C:3]=1[CH3:10].[CH:11]([C:13]1([CH3:26])[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)=O>>[I:1][C:2]1[NH:6][C:11]([C:13]2([CH3:26])[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)=[N:4][C:3]=1[CH3:10]
Reactant: Cc1nc(C(C)C)[nH]c1I
Reactant: CC1(C=O)CCN(C(=O)OC(C)(C)C)CC1
Product: Cc1nc(C2(C)CCN(C(=O)OC(C)(C)C)CC2)[nH]c1I

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 159.2, except tert-butyl 4-formyl-4-methylpiperidine-1-carboxylate was used in place of isobutyraldehyde. m/z (ES+) 406 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:35])[C@@H:4]([N:11]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([CH2:22][C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][C:30]=3[CH3:32])[N:25]([CH3:33])[CH:24]=2)[C:12]1=[O:34])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>O1CCOCC1.O>[CH3:33][N:25]1[C:26]2[C:31](=[C:30]([CH3:32])[CH:29]=[CH:28][CH:27]=2)[C:23]([CH2:22][N:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:20](=[O:21])[N:11]([C@@H:4]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:3]([OH:35])=[O:2])[C:12]2=[O:34])=[CH:24]1
Reactant: COC(=O)[C@H](c1ccccc1)n1c(=O)c2ccccc2n(Cc2cn(C)c3cccc(C)c23)c1=O
Solvent: O
Solvent: C1COCCO1
Product: Cc1cccc2c1c(Cn1c(=O)n([C@H](C(=O)O)c3ccccc3)c(=O)c3ccccc31)cn2C
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To a solution of (S)-[1-(1,4-dimethyl-1H-indol-3-ylmethyl)-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]-phenyl-acetic acid methyl ester (100 mg, 0.21 mmol) in dioxane (2.5 ml) is added a solution of LiOH monohydrate (25 mg, 0.60 mmol) in H2O (2.5 mL). The solution is stirred at 60° C. for 4 hours. The reaction mixture is allowed to cool to room temperature, quenched with 4M HCl in dioxane (500 μL) and is concentrated. The resulting residue is purified by flash chromatography with 10% MeOH in dichloromethane as the eluent to afford the title compound. LCMS (ESMS): m/z 454.19 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH2:7][C:8]([O:10]C)=[O:9])[C:4]([O:12][CH2:13][C:14]2[CH:15]=[N:16][C:17]([O:20][CH2:21][C:22]3[N:23]=[C:24]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[S:25][C:26]=3[CH3:27])=[CH:18][CH:19]=2)=[N:3]1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH3:1][N:2]1[CH:6]=[C:5]([CH2:7][C:8]([OH:10])=[O:9])[C:4]([O:12][CH2:13][C:14]2[CH:15]=[N:16][C:17]([O:20][CH2:21][C:22]3[N:23]=[C:24]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[S:25][C:26]=3[CH3:27])=[CH:18][CH:19]=2)=[N:3]1
Reactant: COC(=O)Cc1cn(C)nc1OCc1ccc(OCc2nc(-c3ccccc3)sc2C)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1sc(-c2ccccc2)nc1COc1ccc(COc2nn(C)cc2CC(=O)O)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.3 %

Procedure:
A mixture of methyl [1-methyl-3-[6-(5-methyl-2-phenyl-4-thiazolylmethoxy)-3-pyridylmethoxy]-1H-pyrazol-4-yl]acetate (497 mg), 1N aqueous sodium hydroxide solution (2 ml), tetrahydrofuran (4 ml) and ethanol (4 ml) was stirred at room temperature for 2 hrs. 1N Hydrochloric acid (2 ml) was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration to give [1-methyl-3-[6-(5-methyl-2-phenyl-4-thiazolylmethoxy)-3-pyridylmethoxy]-1H-pyrazol-4-yl]acetic acid (411 mg, yield 85%), which was then recrystallized from ethanol-hexane. melting point: 140–141° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.[CH2:12]([N:15]=[C:16]=[O:17])[CH:13]=[CH2:14].C(OCC)C>C1COCC1>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH:9][C:16]([NH:15][CH2:12][CH:13]=[CH2:14])=[O:17])=[O:7])=[CH:4][CH:3]=1
Reactant: NNC(=O)c1ccc(Cl)cc1
Reactant: C=CCN=C=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CCNC(=O)NNC(=O)c1ccc(Cl)cc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
At 50° C., 5.00 g (29.3 mmol) of 4-chlorobenzohydrazide were suspended in 150 ml of dry THF. 2.63 ml (29.9 mmol) of allyl isocyanate, dissolved in 110 ml of dry THF, were then added dropwise. Initially, all of the starting material dissolved, and then a fine precipitate formed. The mixture was stirred at 50° C. for 2 h. After cooling to room temperature, diethyl ether was added. The colorless solid was filtered off with suction, washed with diethyl ether and dried under high vacuum. This gave 7.42 g (100% of theory) of the target compound.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([F:19])=[C:6]([CH:13]([O:17][CH3:18])[C:14]([OH:16])=O)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].[NH2:20][CH2:21][C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=1>>[C:21]([C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH:27][C:14](=[O:16])[CH:13]([C:6]2[CH:7]=[CH:8][C:9]([O:10][CH2:11][CH3:12])=[C:4]([O:3][CH2:1][CH3:2])[C:5]=2[F:19])[O:17][CH3:18])=[CH:24][CH:23]=1)#[N:20]
Reactant: N#Cc1ccc(CN)cc1
Reactant: CCOc1ccc(C(OC)C(=O)O)c(F)c1OCC
Product: CCOc1ccc(C(OC)C(=O)NCc2ccc(C#N)cc2)c(F)c1OCC

Procedure:
(RS)-(3,4-Diethoxy-2-fluoro-phenyl)-methoxy-acetic acid was coupled with 4-aminomethyl benzonitrile according to general procedure B to give (RS)-N-(4-cyano-benzyl)-2-(3,4-diethoxy-2-fluoro-phenyl)-2-methoxy-acetamide. Colorless solid. MS 387.3 ([M+H]+)
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20]COC)=[O:19].[S:24](Cl)([CH3:27])(=[O:26])=[O:25]>N1C=CC=CC=1.Cl>[S:24]([NH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])([CH3:27])(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: COCOC(=O)CCCCCCc1ccc2ccccc2c1N
Agent: Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1c(CCCCCCC(=O)O)ccc2ccccc12
Temperature: 50 °C
Reaction time: 2 h
Yield: 84.5 %

Procedure:
In pyridine (3 ml) was dissolved methoxymethyl 7-(1-amino-2-naphthyl)heptanoate (0.3 g) followed by addition of mesyl chloride (0.218 g), and the mixture was stirred at 50° C. for 2 hours. This reaction mixture was poured in 0.5N HCl and extracted with ethyl acetate. The organic layer was washed with water, dried, and concentrated to dryness. The residue was treated with 1N HCl (3 ml) and tetrahydrofuran (6 ml) at the reflux temperature for 1.5 hours and, after cooling, extracted with ethyl acetate. The organic layer was washed with water, dried, and concentrated to dryness, and the residue was recrystallized from hexane-diisopropyl ether to provide 7-(1-mesylamino-2-naphthyl)heptanoic acid (0.281 g).
Reaction SMILES: Cl[Sn](Cl)(Cl)Cl.[CH3:6][C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=1[OH:16].C(O[C@@H:21]1[O:38][C@H:37]([CH2:39][O:40][C:41](=[O:43])[CH3:42])[C@H:32]([O:33][C:34](=[O:36])[CH3:35])[C@H:27]([O:28][C:29](=[O:31])[CH3:30])[C@H:22]1[O:23][C:24](=[O:26])[CH3:25])(=O)C>O>[C:24]([O:23][C@@H:22]1[C@@H:27]([O:28][C:29](=[O:31])[CH3:30])[C@@H:32]([O:33][C:34](=[O:36])[CH3:35])[C@@H:37]([CH2:39][O:40][C:41](=[O:43])[CH3:42])[O:38][C@@H:21]1[O:16][C:8]1[CH:9]=[CH:10][C:11]([N+:13]([O-:15])=[O:14])=[CH:12][C:7]=1[CH3:6])(=[O:26])[CH3:25]
Reactant: Cc1cc([N+](=O)[O-])ccc1O
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Product: CC(=O)OC[C@H]1O[C@H](Oc2ccc([N+](=O)[O-])cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Temperature: 60 °C
Reaction time: 12 h

Procedure:
SnCl4 (0.6 ml) is added slowly to a solution of 2-methyl-4-nitrophenol (ref.: J. S. ANDERSON and K. C. BROWN, Synthetic Commun., 13, 233-236, 1983) and 1,2,3,4,6-penta-O-acetyl-β-D-galactose (1 g, 2.56 mmol), kept at room temperature. The reaction mixture is then stirred under nitrogen for 12 hours at 60° C. After hydrolysis in iced water, extraction with CH2Cl2, followed by washing with a saturated solution of sodium bicarbonate and then water, gives 42, which is then purified by chromatography on silica gel (yield=45%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])[N:16]=2)[NH:11][CH:10]=1.CCN=C=NCCCN(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH3:71][N:72]([CH3:81])[CH2:73][CH2:74][N:75]1[CH2:80][CH2:79][NH:78][CH2:77][CH2:76]1>CN(C=O)C>[CH3:71][N:72]([CH3:81])[CH2:73][CH2:74][N:75]1[CH2:80][CH2:79][N:78]([C:21]([C:20]2[CH:24]=[CH:25][CH:26]=[C:18]([C:15]3[N:16]=[C:17]4[C:9]([C:4]5[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=5[O:2][CH3:1])=[CH:10][NH:11][C:12]4=[N:13][CH:14]=3)[CH:19]=2)=[O:22])[CH2:77][CH2:76]1
Reactant: COc1ccccc1-c1c[nH]c2ncc(-c3cccc(C(=O)O)c3)nc12
Reactant: CN(C)CCN1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1-c1c[nH]c2ncc(-c3cccc(C(=O)N4CCN(CCN(C)C)CC4)c3)nc12
Temperature: 70 °C
Reaction time: 5 h
Yield: 17.7 %

Procedure:
To a mixture of 3-[7-(2-Methoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-benzoic acid (35 mg, 0.1 mmol), EDCI (77 mg, 0.40 mmol), HBTU (3.8 mg, 0.01 mmol) and diisopropylethylamine (175 μl, 1.0 mmol) in DMF (1 mL) was added 2-(dimethylamino)ethylpiperzine (55 μl, 0.3 mmol). The mixture was stirred at 70° C. for 5 hours before the solvents were removed. The resulting yellow oil was washed with water, dissolved in DMSO and purified on reverse phase HPLC to afford the title compound (8.6 mg, 12% over 2 steps) as yellow solid. MS: m/z 485.2 [MH+].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:15]1[N:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][N:16]=1.C(N(CC)CC)C>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:15]2[N:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COc1cnc(Cl)nc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1
Temperature: 60 °C
Reaction time: 144 h
Yield: 40.4 %

Procedure:
1.5 g piperazine-1-carboxylic acid tert-butyl ester was added to 1.2 g 2-chlor-5-methoxy-pyrimidine and 2.2 mL triethylamine in 30 mL DMF. The reaction was stirred 6 days at 60° C. The solvent was removed and the residue was dissolved in dichlormethane and extracted with water. The organic layer was washed with a saturated sodium chloride solution and evaporated to give 957 mg desired product. Rt: 0.82 min (method E), (M+H)+: 295
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8](C(Cl)(Cl)Cl)[N:7]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([NH2:20])[N:15]=3)[C:6]=2[CH:21]=1.[F:22][CH2:23][CH2:24][OH:25].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[F:22][CH2:23][CH2:24][O:25][C:8]1[N:7]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH2:20])[N:15]=2)[C:6]2[CH:21]=[C:2]([I:1])[CH:3]=[CH:4][C:5]=2[N:9]=1
Reactant: Nc1nccc(-n2c(C(Cl)(Cl)Cl)nc3ccc(I)cc32)n1
Reactant: OCCF
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1nccc(-n2c(OCCF)nc3ccc(I)cc32)n1
Yield: 17.1 %

Procedure:
A solution of 4-[6-iodo-2-(trichloromethyl)-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine (1 g, 2.20 mmol), 2-fluoroethan-1-ol (900 mg, 14.05 mmol) and cesium carbonate (4.3 g, 13.20 mmol) in N,N-dimethylformamide (10 mL) was stirred for 14 hr at room temperature. The reaction mixture was diluted with 50 mL of ethyl acetate then washed with 5×10 mL of water. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column (ethyl acetate/petroleum ether, 10:1) to afford 150 mg (17%) of 4-[2-(2-fluoroethoxy)-6-iodo-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine as brown oil: LC-MS: m/z=400 (M+H)+.
Reaction SMILES: [I:1][C:2]1[N:3]=[C:4]([C@@H:8]2[CH2:12][CH2:11][C@H:10]([CH3:13])[N:9]2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[NH:5][C:6]=1I.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(O)C.O>[I:1][C:2]1[NH:3][C:4]([C@@H:8]2[CH2:12][CH2:11][C@H:10]([CH3:13])[N:9]2[C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])=[N:5][CH:6]=1
Reactant: C[C@H]1CC[C@@H](c2nc(I)c(I)[nH]2)N1C(=O)OC(C)(C)C
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: C[C@H]1CC[C@@H](c2ncc(I)[nH]2)N1C(=O)OC(C)(C)C
Temperature: 90 °C
Reaction time: 16 h
Yield: 72.9 %

Procedure:
To a solution of (2S,5S)-tert-butyl 2-(4,5-diiodo-1H-imidazol-2-yl)-5-methylpyrrolidine-1-carboxylate (4.28 g, 8.50 mmol) in ethanol (75 mL) and water (75 mL), sodium thiosulfate (10.72 g, 85.1 mmol) was added and the reaction mixture was stirred vigorously for 1 hour at 100° C., 16 hours at 90° C., and 5 hours at 100° C. The reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was washed additionally with ethyl acetate and the organic layers were combined. The organic layer was dried with sodium sulfate, concentrated and the crude material was purified by column chromatography to yield (2S,5S)-tert-butyl 2-(5-iodo-1H-imidazol-2-yl)-5-methylpyrrolidine-1-carboxylate as a white solid (2.34 g, 6.20 mmol, 73%). 1H NMR (400 MHz, cdcl3) δ 7.04 (s, 1H), 4.89 (dd, 1H), 3.92 (m, 1H), 2.91 (s, 1H), 2.18-2.06 (m, 2H), 1.78 (m, 1H), 1.52 (m, 1H), 1.48 (s, 9H), 1.13 (d, 3H).
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][CH2:5][NH2:6].C(=O)(O)[O-].[Na+].[C:12]([O:15][C:16]([CH3:20])([CH3:19])[CH2:17]Br)(=[O:14])[CH3:13]>C(O)C>[C:16]([O:15][C:12](=[O:14])[CH2:13][NH:6][CH2:5][CH2:4][CH2:3][S:2][CH3:1])([CH3:20])([CH3:19])[CH3:17]
Reactant: CC(=O)OC(C)(C)CBr
Reactant: CSCCCN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CSCCCNCC(=O)OC(C)(C)C
Yield: 116.9 %

Procedure:
To a mixture of 3-methylthiopropylamine (30.0 g, 0.285 mol) and sodium bicarbonate (12.0 g, 0.142 mol) in 250 ml of ethanol was added dropwise bromo-t-butyl acetate (27.8 g, 0.142 mol). After 5 hours the ethanol was removed on a rotary evaporator and the residue partitioned between water and chloroform. The chloroform layer was dried, filtered and concentrated to give 36.4 g of crude N-(3-methylthiopropyl)glycine t-butyl ester as an oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15]([Br:26])=[CH:14][C:10]=1[C:11]([OH:13])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:39][O:40][CH2:41][CH2:42][CH2:43][NH2:44]>CN(C=O)C.O>[CH2:1]([O:8][C:9]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:15]([Br:26])=[CH:14][C:10]=1[C:11]([NH:44][CH2:43][CH2:42][CH2:41][O:40][CH3:39])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc(Br)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: COCCCN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: COCCCNC(=O)c1cc(Br)c(OCc2ccccc2)cc1OCc1ccccc1
Reaction time: 2 h
Yield: 98.8 %

Procedure:
2,4-Bis-benzyloxy-5-bromobenzoic acid (13.5 g, 33 mmol) was dissolved in DMF (anhydrous, 100 ml), and carbonyldiimidazole (CDI) (6.1 g, 37 mmol) was added and the resulting solution was stirred at r.t for 2 h. 3-Methoxypropylamine (3.6 g, 40 mmol) solution in DMF (25 ml) was added and the resulting solution was stirred at r.t. until the reaction was complete. The reaction was diluted with water (250 ml), extracted with ethyl acetate (250 ml×3), and the combined organics were washed thoroughly with water to remove DMF and dried over sodium sulfate. After filtration and concentration, the residue was purified by flash chromatography on silica gel to give 2,4-bis-benzyloxy-5-bromo-N-(3-methoxy-propyl)-benzamide (15.8 g, 99%). M.p.: 104-106° C.; 400 MHz 1H NMR (CDCl3) δ: 8.41 (s, 1H), 7.85 (t, J=5.2 Hz, 1H), 7.45-7.32 (m, 10H), 6.53 (s, 1H), 5.14 (s, 2H), 5.09 (s, 2H), 3.47-3.41 (q, J=5.2 Hz, 2H), 3.30 (t, J=6.4 Hz, 2H), 3.22 (s, 3H), 1.72-1.65 (pent, J=6.4 Hz, 2H); LCMS: 484, 486 [M+H].
Reaction SMILES: [Br:1][C:2]1[C:3]([F:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].CCN(C(C)C)C(C)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C(Cl)Cl>[Br:1][C:2]1[C:3]([F:9])=[C:4]([N:5]([S:20]([CH3:19])(=[O:22])=[O:21])[S:20]([CH3:19])(=[O:22])=[O:21])[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(Br)c1F
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)N(c1cccc(Br)c1F)S(C)(=O)=O
Reaction time: 2 h

Procedure:
A solution of 3-bromo-2-fluoroaniline (Intermediate 34-1, 160 mg, 0.842 mmol) and DIEA (0.368 mL, 2.105 mmol) in DCM (3 mL) was stirred at ca. −5° C. and treated with methanesulfonyl chloride (0.098 mL, 1.263 mmol) and stirred at that temperature for 2 h. The mixture was partitioned between DCM and NaHCO3 (aq). The organic phase was washed with brine, dried and concentrated to provide N-(3-bromo-2-fluorophenyl)-N-(methylsulfonyl)methanesulfonamide as a yellow solid (308 mg, quantitative), used without further purification. 1H NMR (400 MHz, chloroform-d) δ 7.70 (1H, ddd, J=8.1, 6.4, 1.5 Hz), 7.33 (1H, ddd, J=8.1, 6.5, 1.6 Hz), 7.15 (1H, td, J=8.1, 1.4 Hz), 3.46 (6H, s). Mass spectrum m/z 363, 365 (M+NH4)+.