Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]([O:17]CC2C=CC=CC=2)=[O:16])=[CH:10][CH:9]=1>CCOC(C)=O.[Pd].[C]>[CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]([OH:17])=[O:16])=[CH:10][CH:9]=1
Reactant: COC(=O)CCCOc1ccc(CC(=O)OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)CCCOc1ccc(CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.8 %

Procedure:
4-(4-Benzyloxycarbonylmethyl-phenoxy)-butyric acid methyl ester (1.4 g, 4.09 mmol) was dissolved in EtOAc (60 ml). Pd/carbon (100 mg) was added and the reaction stirred under a hydrogen atmosphere (balloon) for 16 h at room temperature. The reaction mixture was filtered through a pad of celite and the pad washed with EtOAc. The filtrate was evaporated to dryness to give a white solid (1.03 g, 100% yield). LCMS purity 93%, m/z 253 [M++H]+.
Reaction SMILES: [C:1]([C:5]1[NH:6][C:7]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]3[N:16]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:17]=[CH:18][C:11]=23)=[CH:8][N:9]=1)([CH3:4])([CH3:3])[CH3:2].[C:27](=O)([O-])[O-].[K+].[K+].CN(C=O)C.CI>O>[C:1]([C:5]1[N:9]([CH3:27])[CH:8]=[C:7]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]3[N:16]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:17]=[CH:18][C:11]=23)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)c1ncc(-c2ccnc3c2ccn3COCC[Si](C)(C)C)[nH]1
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc(-c2ccnc3c2ccn3COCC[Si](C)(C)C)nc1C(C)(C)C
Yield: 51 %

Procedure:
To a mixture of 4-(2-tert-butyl-1H-imidazol-5-yl)-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine (0.019 g, 0.000051 mol) and potassium carbonate (0.15 g, 0.0011 mol) in DMF (3 mL, 0.04 mol) was added methyl iodide (0.01 mL, 0.00015 mol) in two portions over 48 hours. Water was then added and the product was extracted with MTBE. The combined extracts were dried with sodium sulfate, filtered, and concentrated in vacuo, then purified by silica gel chromatography (20% ethyl acetate/hexanes) to afford 4-(2-tert-butyl-1-methyl-1H-imidazol-4-yl)-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine (10 mg, 51%).
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](=[O:22])[N:19]([CH2:23][CH2:24][NH:25][CH3:26])[C:18]4=[O:27])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:30]([F:33])([F:32])[F:31])[CH:3]=1.[N:34]1([S:39](Cl)(=[O:41])=[O:40])[CH2:38][CH2:37][CH2:36][CH2:35]1>>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:27])[N:19]([CH2:23][CH2:24][N:25]([CH3:26])[S:39]([N:34]5[CH2:38][CH2:37][CH2:36][CH2:35]5)(=[O:41])=[O:40])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:30]([F:31])([F:33])[F:32])[CH:3]=1
Reactant: O=S(=O)(Cl)N1CCCC1
Reactant: CNCCN1C(=O)SC(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O
Product: CN(CCN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O)S(=O)(=O)N1CCCC1

Procedure:
N-{2-[(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]ethyl}-N-methylpyrrolidine-1-sulfonamide was prepared from 5-[1-(4-chloro-2-trifluoromethylbenzyl)-1H-indazol-5-ylmethylene]-3-(2-methylaminoethyl)thiazolidine-2,4-dione (from Example 394) and pyrrolidine-1-sulfonyl chloride following General Procedure U.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH2:34]([O:36][CH2:37][CH2:38][O:39][C:40]1[CH:41]=[C:42](/[CH:47]=[C:48](\[O:54][CH2:55][CH3:56])/[C:49]([O:51][CH2:52][CH3:53])=[O:50])[CH:43]=[CH:44][C:45]=1I)[CH3:35].[CH3:57][N:58]([C:67]1[CH:68]=[C:69](B(O)O)[CH:70]=[CH:71][CH:72]=1)[C:59]([NH:61][CH2:62][CH2:63][CH2:64][CH2:65][CH3:66])=[O:60]>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.O>[CH2:55]([O:54]/[C:48](=[CH:47]\[C:42]1[CH:43]=[CH:44][C:45]([C:69]2[CH:70]=[CH:71][CH:72]=[C:67]([N:58]([CH3:57])[C:59]([NH:61][CH2:62][CH2:63][CH2:64][CH2:65][CH3:66])=[O:60])[CH:68]=2)=[C:40]([O:39][CH2:38][CH2:37][O:36][CH2:34][CH3:35])[CH:41]=1)/[C:49]([O:51][CH2:52][CH3:53])=[O:50])[CH3:56]
Reactant: CCCCCNC(=O)N(C)c1cccc(B(O)O)c1
Reactant: CCOCCOc1cc(/C=C(\OCC)C(=O)OCC)ccc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(\OCC)C(=O)OCC)cc2OCCOCC)c1
Temperature: 90 °C
Yield: 9.2 %

Procedure:
29 mg (0.08 mmol) of 2-(dicyclohexylphosphino)biphenyl and 9.3 mg (0.04 mmol) of palladium acetate and then 1.35 mL (2.7 mmol) of aqueous 2 M potassium phosphate solution are added to a solution of 0.9 g (2.07 mmol) of ethyl (Z)-3-[3-(2-ethoxyethoxy)-4-iodophenyl]-2-ethoxyacrylate and 0.58 g (2.5 mmol) of 3-(1-methyl-3-pentylureido)phenylboronic acid (prepared according to Example 24h) in 10 mL of dimethylformamide. The reaction medium is heated at 90° C. for 3 hours. After addition of 20 mL of water and extraction with ethyl acetate, the organic phases are combined, washed with saturated sodium chloride solution and dried over sodium sulfate. After evaporating under vacuum, the residue obtained is purified by chromatography on a column of silica eluted with an 80/20 heptane/ethyl acetate mixture. 100 mg (12%) of ethyl (Z)-2-ethoxy-3-[2-(2-ethoxyethoxy)-3′-(1-methyl-3-pentylureido)biphenyl-4-yl]acrylate are obtained.
Reaction SMILES: [CH:1]1([CH2:7][NH2:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[Cl:18][C:19]1[N:24]=[C:23](Cl)[C:22]([N+:26]([O-:28])=[O:27])=[CH:21][N:20]=1>ClCCl>[Cl:18][C:19]1[N:24]=[C:23]([NH:8][CH2:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:22]([N+:26]([O-:28])=[O:27])=[CH:21][N:20]=1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: NCC1CCCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=[N+]([O-])c1cnc(Cl)nc1NCC1CCCCC1
Yield: 25.6 %

Procedure:
Cyclohexylmethylamine (3.11 g) and N,N-diisopropylethylamine (6.2 ml) were dissolved into 45 ml dichloromethane. The mixture was added dropwise to a solution of 2,4-dichloro-5-nitropyrimidine (4.85 g) in dichloromethane (30 ml) at 0° C. After the completion of the dropwise addition, the mixture was kept at the same temperature to react for 20 min. Purification was conducted by a column chromatography to obtain a bright-yellow sheet-like solid (1.73 g) in a yield of 26%. ESI-MS (m/z, %) 272 (M−H)+. 1H NMR (400 MHz, CDCl3): δ 9.03 (s, 1H), 8.48 (s, 1H), 3.52 (m, 2H), 1.78-1.64 (m, 7H), 1.33-1.14 (m, 4H), 1.08-1.00 (m, 2H).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][CH:7]=[C:8]2[C:13]=1[C:12](=[O:14])[N:11]([C:15]1[CH:20]=[C:19]([S:21]([N:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH2:27][CH2:26][CH2:25]3)(=[O:23])=[O:22])[CH:18]=[CH:17][C:16]=1[Cl:34])[C:10](=[O:35])[NH:9]2)=[O:4].O1CCCC1.O.[OH-].[Li+].Cl>CO>[C:3]([C:5]1[S:6][CH:7]=[C:8]2[C:13]=1[C:12](=[O:14])[N:11]([C:15]1[CH:20]=[C:19]([S:21]([N:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH2:27][CH2:26][CH2:25]3)(=[O:22])=[O:23])[CH:18]=[CH:17][C:16]=1[Cl:34])[C:10](=[O:35])[NH:9]2)([OH:4])=[O:2]
Reactant: COC(=O)c1scc2[nH]c(=O)n(-c3cc(S(=O)(=O)N4CCCc5ccccc54)ccc3Cl)c(=O)c12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1scc2[nH]c(=O)n(-c3cc(S(=O)(=O)N4CCCc5ccccc54)ccc3Cl)c(=O)c12
Temperature: 60 °C
Reaction time: 8 h
Yield: 92.4 %

Procedure:
To a solution of 5-methoxycarbonyl-3-[2-chloro-5-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)phenyl]thieno[3,4-d]-pyrimidine-2,4(1H,3H)-dione (0.2 g) in methanol (12 mL) -tetrahydrofuran (4 mL) was added lithium hydroxide-monohydrate (0.16 g), and the mixture was stirred at 60° C. overnight. To the reaction mixture was added 1 mol/L hydrochloric acid, and the precipitated crystals were collected by filtration. The crystals were washed with water and dried under reduced pressure to give the title compound (0.18 g).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][N:7]=2)[N:3]=[CH:2]1.Br.Br[CH2:16][CH2:17][CH2:18][N:19]([CH3:21])[CH3:20]>>[CH3:20][N:19]([CH3:21])[CH2:18][CH2:17][CH2:16][N:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][N:7]=2)[N:3]=[CH:2]1
Reactant: N#Cc1ccnc(-c2c[nH]cn2)c1
Reactant: CN(C)CCCBr
Agent: Br
Product: CN(C)CCCn1cnc(-c2cc(C#N)ccn2)c1

Procedure:
The title compound was prepared from 2-(1H-imidazol-4-yl)pyridine-4-carbonitrile and (3-bromopropyl)dimethylamine hydrogen bromide according to the procedure for the preparation of Example 35, part A. [M+H] Calc'd for C14H17N5, 256. Found, 256.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:18][C@H:19]([CH3:22])[CH2:20][OH:21])=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:17])=[O:16])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[CH3:23][Si:24]([CH3:44])([CH3:43])[CH2:25][CH2:26][S:27]([N:30]=C1CCCCI1C1C=CC=CC=1)(=[O:29])=[O:28]>C(#N)C>[Br:1][C:2]1[C:3]([NH:18][C@H:19]([CH3:22])[CH2:20][OH:21])=[N:4][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([S:15]([CH3:17])(=[N:30][S:27]([CH2:26][CH2:25][Si:24]([CH3:44])([CH3:43])[CH3:23])(=[O:29])=[O:28])=[O:16])=[CH:13][CH:14]=2)=[N:6][CH:7]=1
Reactant: C[Si](C)(C)CCS(=O)(=O)N=C1CCCCI1c1ccccc1
Reactant: C[C@H](CO)Nc1nc(Nc2ccc(S(C)=O)cc2)ncc1Br
Solvent: CC#N
Product: C[C@H](CO)Nc1nc(Nc2ccc(S(C)(=O)=NS(=O)(=O)CC[Si](C)(C)C)cc2)ncc1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27.2 %

Procedure:
50 mg (0.13 mmol) of (R)-2-[5-bromo-2-{(RS)-4-methylsulfinyl-phenylamino}-pyrimidin-4-ylamino]-propan-1-ol in 3 ml of acetonitrile is mixed with a spatula tip full of CuPF6[CH3CN]4 (about 0.05 equivalent) and stirred for 30 minutes at room temperature. The mixture is cooled in an ice bath, mixed with 55 mg (0.13 mmol) of [N-(2-(trimethylsilyl)ethanesulfonyl)imino]phenyliodinane, and stirred for 4 hours at room temperature. It is cooled again in the ice bath, mixed with a spatula tip full of CuPF6[CH3CN]4 and with 22 mg (0.06 mmol) of [N-(2-(trimethylsilyl)ethanesulfonyl)-imino]phenyliodinane and stirred for another 3 hours at room temperature. The mixture is evaporated to the dry state, and the remaining residue is purified by chromatography. 20 mg of (RS)—S-[4-({5-bromo-4-[(R)-(2-hydroxy-1-methylethyl)amino]pyrimidin-2-yl}amino)phenyl]-S-methyl-N-[2-(trimethylsilyl)ethylsulfonyl]sulfoximide with a melting point of 194-197° C. is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:17])[N:11]([CH2:13][C:14]([OH:16])=O)[CH:12]=2)=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[F:40][C:41]([F:53])([F:52])[C:42]1[CH:43]=[C:44]([C:48]([NH2:51])([CH3:50])[CH3:49])[CH:45]=[CH:46][CH:47]=1>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:9][C:10](=[O:17])[N:11]([CH2:13][C:14]([NH:51][C:48]([CH3:50])([C:44]3[CH:45]=[CH:46][CH:47]=[C:42]([C:41]([F:40])([F:52])[F:53])[CH:43]=3)[CH3:49])=[O:16])[CH:12]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(N)c1cccc(C(F)(F)F)c1
Reactant: O=C(O)Cn1cc(-c2ccc(Cl)cc2)[nH]c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(NC(=O)Cn1cc(-c2ccc(Cl)cc2)[nH]c1=O)c1cccc(C(F)(F)F)c1
Reaction time: 0.17 h

Procedure:
318 mg (1.26 mmol) of [4-(4-chlorophenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl]-acetic acid from Example 233A are placed in 10 ml DMF and treated with 221 mg (1.64 mmol) of HOBt and 314 mg (1.64 mmol) of EDC hydrochloride. After 10 mins' stirring, 332 mg (1.64 mmol) of 1-methyl-1-[(3-trifluoromethyl)phenyl]ethylamine from Example 1A are added and the mixture is stirred overnight at room temperature. For the workup, the reaction mixture is stirred with 100 ml water. Next, the resulting precipitate is suction-filtered, washed with water and dried under high vacuum. Further purification is effected by preparative HPLC [Method 10]. 209 mg (38% of theory) of the target compound are thus obtained.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].C(N(CC)CC)C.Cl[CH2:18][CH2:19][S:20]([F:23])(=[O:22])=[O:21]>C1C=CC=CC=1>[F:23][S:20]([CH2:19][CH2:18][N:3]([CH2:1][CH3:2])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:22])=[O:21]
Reactant: O=S(=O)(F)CCCl
Reactant: CCNc1ccccc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCN(CCS(=O)(=O)F)c1ccccc1

Procedure:
N-Ethylaniline (48.4 g 0.4 m), triethylamine (40.4 g 0.4 m) and benzene (100 ml) are stirred together at room temperature and 2-chloroethanesulfonyl fluoride (58.6 g, 0.4 m) is added dropwise. The reaction mixture is heated at reflux for 1.5 hr. after the addition is completed. The reaction mixture is cooled and filtered to remove any insoluble salts, and the benzene is removed by distillation. The crude product is drowned into hexane (150 ml) and purified by filtration and washing with hexane. The product melts at 48°-50° C.
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][C:5]1[C:13]([O:14][CH2:15][CH2:16][F:17])=[CH:12][CH:11]=[CH:10][C:6]=1[C:7](O)=[O:8].C(Cl)(=O)C(Cl)=O.[OH-].[NH4+:25]>CN(C)C=O.C(OCC)C.C(Cl)Cl>[F:1][CH2:2][CH2:3][O:4][C:5]1[C:13]([O:14][CH2:15][CH2:16][F:17])=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([NH2:25])=[O:8]
Reactant: [NH4+]
Reactant: O=C(O)c1cccc(OCCF)c1OCCF
Agent: O=C(Cl)C(=O)Cl
Agent: [OH-]
Solvent: CCOCC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: NC(=O)c1cccc(OCCF)c1OCCF
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 1.3 gram (0.0054 mole) of 2,3-di(2-fluoroethoxy)benzoic acid, 1.0 gram (0.0080 mole) of oxalyl chloride, and one drop of N,N-dimethylformamide in 20 ml of diethyl ether was stirred at room temperature for approximately 18 hours. The solvent was evaporated from the reaction mixture leaving a residue. This residue was dissolved in 100 ml of methylene chloride, and the resulting organic solution was added slowly to a stirred, cold (0° C.) aqueous solution of ammonium hydroxide (5 ml of 30% solution). This mixture was allowed to warm to room temperature and stir for approximately 18 hours. The mixture was washed with an aqueous, sodium bicarbonate solution followed by an aqueous, saturated sodium chloride solution. The washed organic phase was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure leaving a solid residue. Recrystallization of this solid from a mixture of toluene and n-hexane yielded 0.6 gram of 2,3-di(2-fluoroethoxy)benzamide, mp 100°-101° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4](/[CH:8]=[N:9]/[NH:10]S(C2C=CC(C)=CC=2)(=O)=O)[CH:3]=1>N1CCOCC1.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[N:10]=[N:9][CH:8]=[C:4]2[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)N/N=C/c2cc(Br)ccn2)cc1
Solvent: CCOC(C)=O
Solvent: C1COCCN1
Product: Brc1ccn2nncc2c1
Temperature: 25 °C
Yield: 99.1 %

Procedure:
A solution of (E)-N′-((4-bromopyridin-2-yl)methylene)-4-methylbenzenesulfonohydrazide (compound 40.1, 3.8 g, 10.7 mmol) in morpholine (12 mL) was heated at 130° C. for 3 hours. The reaction mixture was cooled to room temperature, then diluted with EtOAc (150 mL) and washed with water (2×30 mL). The organic layer was dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexanes:EtOAc 4:1) to yield 2.10 g (99%) of the title compound as a light yellow solid. m/z (ES+) 198, 200 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:13]=[C:12]([S:14](Cl)(=[O:16])=[O:15])[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:5]=1[N+:18]([O-:20])=[O:19].[CH3:22][NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41].C(N(CC)CC)C>O1CCCC1>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:13]=[C:12]([S:14](=[O:16])(=[O:15])[N:23]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH3:22])[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:5]=1[N+:18]([O-:20])=[O:19]
Reactant: CCCCCCCCCCCCCCCCCCNC
Reactant: COC(=O)c1cc(S(=O)(=O)Cl)cc(C(=O)OC)c1[N+](=O)[O-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCCN(C)S(=O)(=O)c1cc(C(=O)OC)c([N+](=O)[O-])c(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Solid dimethyl-2-nitro-5-chlorosulfonylisophthalate (2.78 g.) is added in portions to a stirred solution of 2.5 g. of N-methyloctadecylamine and 1.0 g. of triethylamine in 50 ml. of tetrahydrofuran. After the addition the reaction is stirred at room temperature for 30 min. The precipitated amine hydrochloride is removed by filtration and the filtrate concentrated under reduced pressure. The residue is recrystallized from acetonitrile, giving 2.7 g. of product, m.p. 70°-72° C. Additional material is obtained by concentration of the mother liquor.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([N:10]2[C:14]3=[N:15][C:16]([CH3:29])=[CH:17][C:18]([N:19]4[CH2:24][CH2:23][CH:22]([CH2:25][C:26]([OH:28])=[O:27])[CH2:21][CH2:20]4)=[C:13]3[C:12]([CH3:30])=[CH:11]2)=[C:5]([CH3:31])[CH:4]=1.[C:32](=[O:44])([O:37][CH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1)[O:33][CH:34](Cl)[CH3:35].C(=O)([O-])[O-].[K+].[K+].[Na+].[I-]>CN(C=O)C.O>[CH:38]1([O:37][C:32]([O:33][CH:34]([O:27][C:26](=[O:28])[CH2:25][CH:22]2[CH2:21][CH2:20][N:19]([C:18]3[CH:17]=[C:16]([CH3:29])[N:15]=[C:14]4[N:10]([C:6]5[C:7]([CH3:9])=[CH:8][C:3]([Br:2])=[CH:4][C:5]=5[CH3:31])[CH:11]=[C:12]([CH3:30])[C:13]=34)[CH2:24][CH2:23]2)[CH3:35])=[O:44])[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1
Reactant: CC(Cl)OC(=O)OC1CCCCC1
Reactant: Cc1cc(N2CCC(CC(=O)O)CC2)c2c(C)cn(-c3c(C)cc(Br)cc3C)c2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(N2CCC(CC(=O)OC(C)OC(=O)OC3CCCCC3)CC2)c2c(C)cn(-c3c(C)cc(Br)cc3C)c2n1
Temperature: 60 °C
Yield: 59.3 %

Procedure:
A suspension of {1-[1-(4-bromo-2,6-dimethyl-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-acetic acid hydrochloride (300 mg), 1-chloroethyl cyclohexyl carbonate (293 mg), potassium carbonate (196 mg) and NaI (213 mg) in DMF (3 mL) was heated at 60° C. for 3 hours. After cooling to room temperature, water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with brine and concentrated under reduced pressure. The residue was purified with column chromatography (silica gel: Wako gel C200, eluent: hexane:ethyl acetate=4/1) to obtain the title compound (225 mg) as a colorless oil.
Reaction SMILES: [F:1][CH:2]([F:32])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[C:29]([O:30][CH3:31])[C:5]=2[N:4]=1.Cl.Cl.[CH3:35][N:36]([CH3:49])[CH2:37][CH2:38][CH2:39][S:40](N1CCNCC1)(=[O:42])=[O:41].CCN(C(C)C)C(C)C>CS(C)=O.O>[F:32][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=[C:10]([N:20]3[CH2:25][CH2:24][N:23]([S:40]([CH2:39][CH2:38][CH2:37][N:36]([CH3:49])[CH3:35])(=[O:42])=[O:41])[CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[C:29]([O:30][CH3:31])[C:5]=2[N:4]=1
Reactant: CN(C)CCCS(=O)(=O)N1CCNCC1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCNCC2)nc(N2CCOCC2)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CCN(S(=O)(=O)CCCN(C)C)CC2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.4 %

Procedure:
A mixture of 2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(1-piperazinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (Example 2) (150 mg, 0.378 mmol), N,N-dimethyl-3-(1-piperazinylsulfonyl)-1-propanamine dihydrochloride (WO 2006/046040) (151 mg, 0.491 mmol), and DIPEA (0.40 mL, 2.27 mmol) in DMSO was stirred at room temperature for 30 minutes. The reaction mixture was diluted with water; and the resulting precipitate was collected by filtration, washed with water, and dissolved in CH2Cl2. The solution was dried (Na2SO4) and the solvent removed under vacuum. Chromatography on silica eluting with CH2Cl2/MeOH (95:5), followed by additional chromatography on silica eluting with CH2Cl2/MeOH (96:4) gave N-[3-({4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperazinyl}sulfonyl)propyl]-N,N-dimethylamine (91 mg, 40%). Treatment with 1.25 M HCl solution in MeOH and recrystallization from MeOH/EtOAc gave the hydrochloride salt: mp 209-211° C.; 1H NMR (DMSO-d6) δ10.16 (br s, 1H), 7.89 (d, J=8.4 Hz, 1H), 7.69 (t, JHF=52.9 Hz, 1H), 7.41 (t, J=8.2 Hz, 1H), 6.96 (d, J=7.8 Hz, 1H), 3.98 (s, 3H), 3.94 (m, 4H), 3.82 (m, 4H), 3.70 (br s, 4H), 3.33 (m, 4H), 3.23 (dd, J=9.3, 5.8 Hz, 2H), 3.12 (m, 2H), 2.75 (s, 6H), 2.08 (td, J=15.4, 7.8 Hz, 2H); Anal. Calcd. for C25H36ClF2N9O4S.0.5H2O: C, 46.8; H, 5.8; N, 19.7. Found: C, 46.9; H, 5.8; N, 19.4%.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][N:4]=1.O.[Na].Cl[C:15]1[N:20]=[C:19]([OH:21])[C:18]([N+:22]([O-:24])=[O:23])=[CH:17][N:16]=1>C(O)C.[Ni].O>[OH:21][C:19]1[C:18]([N+:22]([O-:24])=[O:23])=[CH:17][N:16]=[C:15]([NH:9][C:6]2[CH:5]=[N:4][C:3]([S:2][CH3:1])=[CH:8][CH:7]=2)[N:20]=1
Reactant: CSc1ccc([N+](=O)[O-])cn1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1O
Agent: [Ni]
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CSc1ccc(Nc2ncc([N+](=O)[O-])c(O)n2)cn1

Procedure:
4.5 gm (0.0264 mol) of 2-methylthio-5-nitro-pyridine were hydrogenated at 50° C. and 5 bars pressure in ethanol in the presence of Raney nickel as the catalyst. After the catalyst had been filtered off and after evaporation of the filtrate in vacuo an oil was obtained. A solution of 6.84 gm (0.032 mol) of the sodium monohydrate salt of 2-chloro-4-hydroxy-5-nitro pyrimidine in 150 ml of water was added to the solution of this oil in water. The aqueous solution was heated for 30 minutes on a steam bath, and the resulting precipitate suction-filtered off, washed with water and dried. 4-Hydroxy-2-(6'-methylmercapto-3-pyridyl)amino-5-nitro-pyrimidine was obtained.
Reaction SMILES: [CH3:1][C:2]12[CH2:11][N:10](C(OCC3C=CC=CC=3)=O)[CH2:9][CH2:8][N:7]1[CH2:6][CH:5]([C:22]1[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=1)[C:28](=[O:32])[O:27][C@@H:26]([CH3:33])[CH2:25]3)[O:4][CH2:3]2>CO.[Pd]>[CH3:33][C@H:26]1[CH2:25][C:24]2[C:29](=[CH:30][CH:31]=[C:22]([CH:5]3[O:4][CH2:3][C:2]4([CH3:1])[CH2:11][NH:10][CH2:9][CH2:8][N:7]4[CH2:6]3)[CH:23]=2)[C:28](=[O:32])[O:27]1
Reactant: C[C@H]1Cc2cc(C3CN4CCN(C(=O)OCc5ccccc5)CC4(C)CO3)ccc2C(=O)O1
Agent: [Pd]
Solvent: CO
Product: C[C@H]1Cc2cc(C3CN4CCNCC4(C)CO3)ccc2C(=O)O1
Reaction time: 16 h

Procedure:
The mixture of Benzyl 9a-methyl-3-((S)-3-methyl-1-oxoisochroman-6-yl)hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-carboxylate (215 mg, 0.500 mmol) and 10% Pd-C (56 mg, 0.05 mmol) in MeOH (10 mL) was stirred under a hydrogen balloon for 16 h. After which point, the solution was filtered through Celite and the resulting filtrate was concentrated to afford the title compound: LC/MS: m/e 317.2 (M+H)+.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:8]=[CH:7][NH:6][C:5]=1[C:9]([O:11][CH3:12])=[O:10].Cl.C[N:15](C=O)C>[Li+].[Cl-].O1CCOCC1.CCOCC>[ClH:3].[NH2:15][N:6]1[CH:7]=[CH:8][C:4]([Cl:3])=[C:5]1[C:9]([O:11][CH3:12])=[O:10]
Reactant: CN(C)C=O
Reactant: COC(=O)c1[nH]ccc1Cl
Agent: Cl
Agent: [Cl-]
Agent: [H-]
Solvent: C1COCCO1
Solvent: CCOCC
Product: COC(=O)c1c(Cl)ccn1N
Reaction time: 0.42 h
Yield: 99 %

Procedure:
A mixture of sodium hydride (60%, 0.8 g, 20 mmol) and methyl 3-chloro-1H-pyrrole-2-carboxylate (Tetrahedron, 1999, 55, 4133–4152; 2.5 g, 15.7 mmol) in DMF (10 mL) at 0° C. was stirred for 25 min, then was added 2,4-dinitrophenolamine (Tetrahedron Lett. 1968, 16, 1909–1910 and J. Heterocyclic Chem. 1967, 413, 3.80 g, 19.1 mmol) and the reaction mixture was stirred at 0–5° C. for 2.5 h. The mixture was diluted with 10% aqueous LiCl solution and the product was extracted with EtOAc (3×100 mL). The EtOAc solution was washed with 10% LiCl solution (2×80 mL), brine (80 mL), dried over MgSO4 and concentrated in vacuo to give the crude product as a brown oil. The crude product was treated with 4 N HCl in dioxane (2 mL) in Et2O (60 mL). The precipitated solid was collected, washed with Et2O and dried in vacuo to obtain the title compound (3.30 g, 99%): 1H NMR (DMSO-d6) δ 7.17 (d, 1H, J=2.2 Hz), 6.68 (d, 1H, J=2.2 Hz), 3.74 (s, 3H).