Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[N:7]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH:8]1[CH2:11][N:10]([S:12]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:26]([NH:7][CH:8]1[CH2:11][N:10]([S:12]([C:15]2[CH:16]=[CH:17][C:18]([NH:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:19][CH:20]=2)(=[O:14])=[O:13])[CH2:9]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCCCNc1ccc(S(=O)(=O)N2CC(N(Cc3ccccc3)C(=O)OC(C)(C)C)C2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCNc1ccc(S(=O)(=O)N2CC(NCc3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.2 %

Procedure:
To a solution of Benzyl-[1-(4-butylamino-benzenesulfonyl)-azetidin-3-yl]-carbamicacid tert-butyl ester (0.19 g, 0.4 mmol) in dichloromethane (4 ml) was added trifluoroacetic acid (0.31 ml, 4 mmol). The mixture was stirred at room temperature for 2 h, and then quenched with saturated sodium carbonate solution, and extracted with dichloromethane. The organic solution was washed with brine, dried over sodium sufate, and evaporated. The crude product was chromatographed on silica gel (ethyl acetate-hexanes/3:2) to give 0.09 g of a colorless foam; MS (ES) m/z 374.1 (MH+); HRMS (El) Calcd. for C20H27N3O2S (M+): 373.1824, Found: 373.1822.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[Na].[C:14]([NH:16][C:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=S)#[N:15]>O1CCCC1>[NH2:15][C:14]1[N:1]=[C:2]2[N:6]([C:17](=[N:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:16]=1)[C:5]1[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:4]=1[S:3]2
Reactant: N#CNC(=S)Nc1ccccc1
Reactant: COc1ccc2nc(N)sc2c1
Agent: [Na]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)sc1nc(N)nc(=Nc3ccccc3)n12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 2-amino-6-methoxy benzothiazole (9.0 g) in dry tetrahydrofuran was treated with the sodium salt of N-cyano-N'-phenyl thiourea (5.0 g) and finely powdered mercuric chloride (6.75 g) and the mixture stirred at room temperature for 24 hours.
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].[F:5][C:6]1[CH:7]=[C:8]([N:18]2[CH2:22][C@H:21]([C:23](Cl)=[O:24])[O:20][C:19]2=[O:26])[CH:9]=[CH:10][C:11]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>O1CCCC1.O>[F:5][C:6]1[CH:7]=[C:8]([N:18]2[CH2:22][C@H:21]([C:23]([NH:4][CH2:1][CH:2]=[CH2:3])=[O:24])[O:20][C:19]2=[O:26])[CH:9]=[CH:10][C:11]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: O=C(Cl)[C@H]1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1
Reactant: C=CCN
Solvent: O
Solvent: C1CCOC1
Product: C=CCNC(=O)[C@H]1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1
Reaction time: 2 h

Procedure:
To a flame-dried flask under nitrogen is added allylamine (0.60 mL, 8.05 mmol). The flask is cooled in an ice bath, and a solution of (5R)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinecarbonyl chloride (EXAMPLE 1, Step 2, 0.805 mmol theory) in anhydrous tetrahydrofuran (8.0 mL) is added. The resulting mixture is stirred under nitrogen for 2 h, allowing the cooling bath to slowly expire, and is then diluted with water (10 mL) and extracted with methylene chloride (20 mL). The organic phase is washed with water (10 mL) and saline (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the crude product is chromatographed on a Flash 40S silica gel (40 g, 32-63 μm) cartridge, eluting with a gradient of methanol/methylene chloride (0.5/99.5-2/98). Pooling and concentration of those fractions with an Rf=0.44 by TLC (methanol/chloroform, 5/95) provides the title compound, mp 167-169° C.; MS (ESI+) for C17H20FN3O4 m/z 350 (M+H)+; [α]25D=−44° (c 0.94, DMSO).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([Cl:7])[C:4]([Cl:8])=[C:3]([C:9]2[N:14]=[N:13][C:12]([NH2:15])=[N:11][C:10]=2[NH2:16])[CH:2]=1.[Cl:17][C:18]1[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21]>N1C=CC=CC=1>[NH2:16][C:10]1[N:11]=[C:12]([NH:15][C:20](=[O:21])[C:19]2[CH:23]=[CH:24][CH:25]=[C:26]([Cl:27])[C:18]=2[Cl:17])[N:13]=[N:14][C:9]=1[C:3]1[CH:2]=[CH:1][CH:6]=[C:5]([Cl:7])[C:4]=1[Cl:8]
Reactant: O=C(Cl)c1cccc(Cl)c1Cl
Reactant: Nc1nnc(-c2cccc(Cl)c2Cl)c(N)n1
Solvent: c1ccncc1
Product: Nc1nc(NC(=O)c2cccc(Cl)c2Cl)nnc1-c1cccc(Cl)c1Cl

Procedure:
Lamotrigine (512.00 g, 2.00 moles) was dissolved in pyridine (3 I) and 2,3-dichlorobenzoyl chloride (873.00 g, 96% pure, equivalent to 838.10 g, 4.00 moles) was added below 35° C. with stirring under anhydrous conditions. The acid chloride was added in two equal portions. The second portion of acid chloride was added after 30 minutes from the start of the reaction and stirred below 35° C. for a further 30 minutes.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[CH:5]1([NH:8][C:9](=[O:39])[C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([N:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]4([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[O:33][CH2:34][C@H:35]5[CH2:37][O:36]5)[CH2:26][CH2:25]4)[C:18]3=[O:38])[CH:11]=2)[CH2:7][CH2:6]1>CN(C=O)C>[CH:5]1([NH:8][C:9](=[O:39])[C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([N:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]4([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[O:33][CH2:34][C@H:35]([OH:36])[CH2:37][NH:4][CH2:3][CH2:1][OH:2])[CH2:25][CH2:26]4)[C:18]3=[O:38])[CH:11]=2)[CH2:6][CH2:7]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(NC2(c3ccccc3OC[C@H]3CO3)CC2)c1=O
Reactant: NCCO
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(NC2(c3ccccc3OC[C@H](O)CNCCO)CC2)c1=O
Temperature: 50 °C

Procedure:
Ethanolamine (1 mL) was added to N-cyclopropyl-4-methyl-3-{3-[(1-{2-[(2R)-oxiran-2-ylmethoxy]phenyl}cyclopropyl)amino]-2-oxopyrazin-1(2H)-yl}benzamide (Example 299a, 7.81 g) in DMF (3 mL). The reaction was heated at 50° C. overnight. The reaction mixture was partitioned between water and DCM. The combined organics were dried (MgSO4), filtered and evaporated. Purification by preparative HPLC (Xbridge column, eluting with a gradient of acetonitrile in 0.2% (v/v) aqueous ammonia) gave the title product (0.102 g) after solvent removal and trituration with diethyl ether.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[N:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])[C:5]2=[O:20].C(OC(=O)C)(=O)C.[CH3:28][C:29]1[S:30][CH:31]=[C:32]([CH:34]=O)[N:33]=1>O.[Cl-].[Zn+2].[Cl-]>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH:12]=[CH:34][C:32]1[N:33]=[C:29]([CH3:28])[S:30][CH:31]=1)[N:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])[C:5]2=[O:20]
Reactant: Cc1nc(C=O)cs1
Reactant: Cc1ccccc1-n1c(C)nc2ccc(F)cc2c1=O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: Cc1nc(C=Cc2nc3ccc(F)cc3c(=O)n2-c2ccccc2C)cs1
Temperature: 25 °C
Yield: 21.2 %

Procedure:
Anhydrous zinc chloride (0.136 g, 1.0 mmol) was fused with a nitrogen purge in a round bottom flask with an open flame. The reaction vessel was allowed to return to ambient temperature, then dioxane (10 mL) was added. To this mixture was added 6-fluoro-2-methyl-3-(2-methyl-phenyl)-3H-quinazolin-4-one (0.134 g, 0.5 mmol), acetic anhydride (0.141 mL, 1.5 mmol), and 2-methylthiazole-4-carboxaldehyde (0.191 g, 1.5 mmol). The reaction was refluxed 3.5 h, cooled to ambient temperature, and diluted with water. The mixture was repeatedly extracted with chloroform. The combined chloroform layer was washed with water and brine and finally dried over sodium sulfate and concentrated to leave a dark residue. This residue was triturated with ether, filtered and dried to afford 0.04 g (21%) of 6-fluoro-2-[2-(2-methyl-thiazol-4-yl)-vinyl]-3-(2-methyl-phenyl)-3H-quinazolin-4-one as tan solid.
Reaction SMILES: [C:1]([NH:8][CH:9]([C:13]([OH:15])=[O:14])[CH2:10][CH2:11][SH:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl[C:17]([F:21])([F:20])[CH2:18][Cl:19]>[OH-].[Na+].CN(C=O)C>[C:1]([NH:8][CH:9]([C:13]([OH:15])=[O:14])[CH2:10][CH2:11][S:12][C:17]([F:21])([F:20])[CH2:18][Cl:19])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)NC(CCS)C(=O)O
Reactant: FC(F)(Cl)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC(CCSC(F)(F)CCl)C(=O)O
Temperature: 50 °C

Procedure:
Ex-18a) A solution of N-Boc-D,L-homocysteine (5 mmol) in NaOH (5 mL, 2N) was slowly added to a stirred solution of 1,2-dichloro-1,1-difluoroethane (5 mmol) in DMF. The resulting solution was then warmed to 50° C. for 16 hours. The reaction solution was then poured onto EtOAc and extracted with citric acid (5%) and brine, dried (Na2SO4) and concentrated in vacuo. The material was purified by flash column chromatography to yield N-Boc-S-(2-chloro-1,1-difluoroethyl)-D,L-homocysteine. Example 18 is prepared in the same manner as described for Example 17 starting with N-Boc-S-(2-chloro-1,1-difluoroethyl)-D,L-homocysteine.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)=[C:13]2[C:17]=1[C:16](=[O:18])[CH:15]([C:19]([O:21][CH3:22])=[O:20])[CH2:14]2.Br[CH2:34][C:35]1[CH:44]=[CH:43][C:38]([C:39]([O:41][CH3:42])=[O:40])=[CH:37][CH:36]=1>CC(C)=O.O>[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:31])([F:30])[F:32])[CH:24]=2)=[C:13]2[C:17]=1[C:16](=[O:18])[C:15]([CH2:34][C:35]1[CH:36]=[CH:37][C:38]([C:39]([O:41][CH3:42])=[O:40])=[CH:43][CH:44]=1)([C:19]([O:21][CH3:22])=[O:20])[CH2:14]2
Reactant: COC(=O)C1Cc2c(-c3cccc(C(F)(F)F)c3)ccc(OC)c2C1=O
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)c1ccc(CC2(C(=O)OC)Cc3c(-c4cccc(C(F)(F)F)c4)ccc(OC)c3C2=O)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 100.4 %

Procedure:
Potassium carbonate (15 mg, 0.11 mmol) was added to a solution of methyl 7-methoxy-1-oxo-4-(3-(trifluoromethyl)phenyl)-2,3-dihydro-1H-indene-2-carboxylate (26 mg, 0.07 mmol) in acetone (1.0 mL). Methyl 4-(bromomethyl)benzoate (32 mg, 0.14 mmol) was added and the mixture was stirred at room temperature. After 4 d, the reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3×20 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The resulting crude residue was purified by combiflash (4 g column, hexanes→EtOAc, gradient) to afford 36 mg (98%) of methyl 7-methoxy-2-(4-(methoxycarbonyl)benzyl)-1-oxo-4-(3-(trifluoromethyl)phenyl)-2,3-dihydro-1H-indene-2-carboxylate.
Reaction SMILES: [ClH:1].[CH2:2]([O:6][CH:7]([O:31][CH2:32][CH2:33][CH2:34][CH3:35])[C@H:8]([CH2:24][CH2:25][CH2:26][NH:27][C:28](=[NH:30])[NH2:29])[NH:9][C:10](=[O:23])[CH2:11][NH:12]C(OCC1C=CC=CC=1)=O)[CH2:3][CH2:4][CH3:5].[H][H]>CO.[Pd]>[ClH:1].[CH2:32]([O:31][CH:7]([O:6][CH2:2][CH2:3][CH2:4][CH3:5])[C@H:8]([CH2:24][CH2:25][CH2:26][NH:27][C:28](=[NH:29])[NH2:30])[NH:9][C:10](=[O:23])[CH2:11][NH2:12])[CH2:33][CH2:34][CH3:35]
Reactant: [H][H]
Reactant: CCCCOC(OCCCC)[C@H](CCCNC(=N)N)NC(=O)CNC(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCCCOC(OCCCC)[C@H](CCCNC(=N)N)NC(=O)CN
Yield: 101.3 %

Procedure:
After N-benzyloxycarbonyl-glycyl-L-argininal dibutylacetal hydrochloride (1.60 g, 3.10 mmols) was dissolved in methanol (250 ml), palladium black (1 g) was added to the solution. The mixture was stirred at room temperature for 2 hours in a hydrogen flow. After completion of the reaction, the catalyst was filtered off and the filtrate was concentrated to give 1.20 g (100%) of glycyl-L-argininal dibutylacetal hydrochloride as oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].C(N(C(C)C)C(C)C)C.C1(C)C=CC(S(O[CH2:31][CH2:32][CH:33]2[CH2:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[O:35][CH2:34]2)(=O)=O)=CC=1>>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH2:31][CH2:32][CH:33]2[CH2:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[O:35][CH2:34]2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCNCC1
Reactant: Cc1ccc(S(=O)(=O)OCCC2COc3ccccc3C2)cc1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CCN(CCC2COc3ccccc3C2)CC1
Reaction time: 16 h
Yield: 97.1 %

Procedure:
First 3.76 g (24 mmol) of piperidine-4-carboxylic acid ethyl ester and then 3.1 g (24 mmol) of N-ethyl-N,N-diisopropylamine are added to a solution of 3.98 g (12 mmol) of 3-[2-(p-toluenesulphonyloxy)ethyl]chroman in 50 ml of absolute diemthylformamide. The mixture is stirred for 16 hours at 60° and, after cooling, is concentrated by evaporation under a high vacuum. Water is added to the oily residue and extraction by shaking is carried out with diethyl ether. The combined organic phases are extracted with 2N hydrochloric acid. The combined hydrochloric acid extracts are rendered alkaline, while cold, with sodium hydroxide solution (30% strength) and extracted with dichloromethane. The combined dichloromethane phases are dried over sodium sulphate and concentrated by evaporation in vacuo. 3.8 g (100%) of crude product are obtained which are chromatographed on 200 g of silica gel (0.040-0.063 mm) using ethyl acetate as the eluant. 3.7 g (97.3%) of 1-[2-(chroman-3-yl)ethyl]piperidine-4-carboxylic acid ethyl ester are then obtained in the form of a colourless oil. The 1-[2-chroman-3-yl)ethyl]-piperidine-4-carboxylic acid ethyl ester hydrochloride produced therefrom using hydrochloric acid in diethyl ether crystallises from ethanol/diethyl ether and melts at 182°-186°.
Reaction SMILES: [CH:1]([C:4]1[CH:35]=[CH:34][C:7]([CH2:8][NH:9][C:10]([C@H:12]2[CH2:17][N:16]([C:18](=[S:20])[NH2:19])[CH2:15][CH2:14][N:13]2[S:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)(=[O:23])=[O:22])=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[C:36]([O:40][C:41](=[O:47])[CH:42](Br)[C:43](=O)[CH3:44])([CH3:39])([CH3:38])[CH3:37]>C(#N)C>[C:36]([O:40][C:41]([C:42]1[S:20][C:18]([N:16]2[CH2:15][CH2:14][N:13]([S:21]([C:24]3[CH:25]=[CH:26][C:27]([C:30]([F:31])([F:33])[F:32])=[CH:28][CH:29]=3)(=[O:22])=[O:23])[C@@H:12]([C:10](=[O:11])[NH:9][CH2:8][C:7]3[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:35][CH:34]=3)[CH2:17]2)=[N:19][C:43]=1[CH3:44])=[O:47])([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(=O)C(Br)C(=O)OC(C)(C)C
Reactant: CC(C)c1ccc(CNC(=O)[C@H]2CN(C(N)=S)CCN2S(=O)(=O)c2ccc(C(F)(F)F)cc2)cc1
Solvent: CC#N
Product: Cc1nc(N2CCN(S(=O)(=O)c3ccc(C(F)(F)F)cc3)[C@@H](C(=O)NCc3ccc(C(C)C)cc3)C2)sc1C(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 85 %

Procedure:
A mixture of the compound (250 mg) obtained in Example 4 and 2-bromo-3-oxobutyric acid tert-butyl ester (168 mg) in acetonitrile (1.25 ml) was stirred at 80° C. for 20 min. The reaction mixture was concentrated under reduced pressure, and the residue was purified by thin layer chromatography (ethyl acetate:n-hexane=2:3) to give the title compound (268 mg).
Reaction SMILES: Cl.C([O:9][C:10](=[O:16])[C@@H:11]1[CH2:15][CH2:14][CH2:13][NH:12]1)C1C=CC=CC=1.[C:17]1([CH2:27][C:28]([OH:30])=O)[CH:22]=[CH:21][C:20]([CH2:23][C:24]([OH:26])=O)=[CH:19][CH:18]=1>CCOC(C)=O>[C:10]([C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:28](=[O:30])[CH2:27][C:17]1[CH:18]=[CH:19][C:20]([CH2:23][C:24]([N:12]2[CH2:13][CH2:14][CH2:15][C@H:11]2[C:10]([OH:9])=[O:16])=[O:26])=[CH:21][CH:22]=1)([OH:16])=[O:9]
Reactant: O=C(O)Cc1ccc(CC(=O)O)cc1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(O)[C@@H]1CCCN1C(=O)Cc1ccc(CC(=O)N2CCC[C@H]2C(=O)O)cc1
Yield: 134.4 %

Procedure:
Using General Procedure A with 1.0 g (4.1 mmol) L-Proline benzyl ester hydrochloride and 400 mg (2.1 mmol) 1,4-phenylenediacetic acid afforded, after flash chromatography (EtOAc), 1.07 g (91%) of the title compound as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)(=O)=O)[C:5]([C:12]#[N:13])=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1.[C:20]1([CH2:26][CH2:27][NH2:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([NH:28][CH2:27][CH2:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:5]([C:12]#[N:13])=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1
Reactant: NCCc1ccccc1
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccccc2)c1C#N
Solvent: COCCOC
Product: N#Cc1c(NCCc2ccccc2)nc(N)nc1-c1ccccc1

Procedure:
From 2-amino-4-methanesulfonyl-6-phenyl-pyrimidine-5-carbonitrile and 2-phenylethylamine in DME. ES-MS m/e (%): 316 (M+H+, 100).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)=[CH:5][CH:4]=1.[NH2:15][C:16]1[N:21]=[N:20][C:19]([N:22]2[CH2:27][CH2:26][N:25]([C:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:36]([F:39])([F:38])[F:37])=[O:29])[CH2:24][CH2:23]2)=[CH:18][CH:17]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][CH2:11][C:12]([NH:15][C:16]2[N:21]=[N:20][C:19]([N:22]3[CH2:23][CH2:24][N:25]([C:28](=[O:29])[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[C:36]([F:39])([F:38])[F:37])[CH2:26][CH2:27]3)=[CH:18][CH:17]=2)=[O:14])=[CH:7][CH:8]=1
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Reactant: COc1ccc(CCCC(=O)O)cc1
Product: COc1ccc(CCCC(=O)Nc2ccc(N3CCN(C(=O)c4ccccc4C(F)(F)F)CC3)nn2)cc1

Procedure:
Following the procedure of Example 1, making variations only as required to use 4-(4-methoxyphenyl)butyric acid in place of 4-methylpentanoic acid to react with [4-(6-aminopyridazin-3-yl)piperazin-1-yl](2-trifluoromethylphenyl)-methanone, the title compound was obtained as a white powder (20% yield). 1H NMR (300 MHz, CDCl3) δ 9.14, 8.29, 7.67, 7.55, 7.49, 7.30, 7.01, 6.98, 6.73, 3.95-3.91, 3.86-3.81, 3.70, 3.61-3.55, 3.48-3.45, 3.26-3.24, 2.57, 2.45, 1.96.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11](Br)[CH:12]=[C:13]([F:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[O:22]1[CH2:27][CH2:26][C:25](=[O:28])[CH2:24][CH2:23]1.[Cl-].[NH4+]>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:25]2([OH:28])[CH2:26][CH2:27][O:22][CH2:23][CH2:24]2)[CH:12]=[C:13]([F:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1cc(Br)cc(OCc2ccccc2)c1
Reactant: O=C1CCOCC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC1(c2cc(F)cc(OCc3ccccc3)c2)CCOCC1
Temperature: -75 °C
Reaction time: 1 h
Yield: 29.4 %

Procedure:
A solution of 3-benzyloxy-1-bromo-5-fluorobenzene (29.1 g) in 250 ml of tetrahydrofuran was cooled to about -75° C. and n-butyl lithium (1.6M in hexane, 65 ml) was added dropwise.. The mixture was stirred at about -75° C. for about 1 hour and a solution of tetrahydropyran-4-one (10.4 g) was added dropwise. The mixture was stirred at about -75° C. for about 1 more hour then allowed to warm to about 0° C. A saturated aqueous solution of ammonium chloride was added and the tetrahydrofuran was evaporated in vacuo. The residue was partitioned between water and ethyl acetate. The organic phase was separated and dried over sodium sulfate. The residue was purified by column chromatography on silica gel eluting with methylene chloride/hexanes to give 9.2 g of the title compound as an oil.
Reaction SMILES: [O:1]1[C:5](B(O)O)=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.[N:13]1([CH2:18][C:19]2[CH:20]=[CH:21][C:22](Br)=[N:23][CH:24]=2)[CH:17]=[CH:16][N:15]=[CH:14]1>>[O:1]1[C:5]([C:22]2[CH:21]=[CH:20][C:19]([CH2:18][N:13]3[CH:17]=[CH:16][N:15]=[CH:14]3)=[CH:24][N:23]=2)=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2
Reactant: Brc1ccc(Cn2ccnc2)cn1
Reactant: OB(O)c1cc2ccccc2o1
Product: c1ccc2oc(-c3ccc(Cn4ccnc4)cn3)cc2c1

Procedure:
Synthesized using benzo[b]furan-2-ylboronic acid (204 mg, 1.26 mmol) and 1a (150 mg, 0.63 mmol) according to Method C. Yellow solid. Yield: 71 mg, 0.26 mmol, 41%. 1H NMR (CDCl3, 500 MHz): δH (ppm): 5.18 (s, 2H), 6.93 (s, 1H), 7.13 (s, 1H), 7.25-7.28 (m, 2H), 7.35 (dt, J=8.2, 1.2 Hz, 1H), 7.44 (d, J=0.9 Hz, 1H), 7.51 (dd, J=8.2, 2.1 Hz, 1H), 7.56 (dd, J=8.2, 0.9 Hz, 1H), 7.60 (s, 1H), 7.65 (d, J=7.3 Hz, 1H), 7.88 (d, J=8.2 Hz, 1H), 8.56 (d, J=2.1 Hz, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=48.1, 105.5, 111.5, 119.0, 119.8, 121.8, 123.3, 125.5, 128.6, 130.4, 130.8, 135.7, 137.3, 148.7, 149.4, 154.3, 155.4; MS (ESI): m/z=276.03 [M+H]+.
Reaction SMILES: [CH3:1][S:2]SC.[C:5]1([CH3:14])[CH:10]=[CH:9][C:8]([S:11]([O-:13])=[O:12])=[CH:7][CH:6]=1.[Na+].II.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[C:5]1([CH3:14])[CH:10]=[CH:9][C:8]([S:11](=[O:13])([S:2][CH3:1])=[O:12])=[CH:7][CH:6]=1
Reactant: Cc1ccc(S(=O)[O-])cc1
Reactant: CSSC
Agent: II
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CSS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 229.3 %

Procedure:
In accordance with the method described in the literature (Synthesis 2002, 343), into a solution (12 mL) of 400 mg (4.25 mmoL) of dimethyl disulfide in methylene chloride were added 2.42 g (13.6 mmoL) of sodium p-toluenesulfinate and 2.16 g (8.50 mmoL) of iodine, followed by stirring at room temperature for 1 hour. The reaction solution was diluted with methylene chloride (12 mL), and a 1 M aqueous sodium thiosulfate solution was added thereto until the iodine color disappeared. The organic layer was washed with water (10 mL), dried over anhydrous magnesium sulfate, and filtered, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to obtain 1.97 g of the heading compound as a colorless powdery substance (yield 100%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[N+:21]([O-])=O.[H][H]>C(O)C.[Pd]>[NH2:21][C:3]1[CH:4]=[CH:5][C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])[CH2:9]2)=[N:7][C:2]=1[NH2:1]
Reactant: [H][H]
Reactant: Nc1nc(N2CCC[C@@H](C(=O)N3CCCC3)C2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N

Procedure:
To a solution of (R)-(1-(6-amino-5-nitropyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone (150 mg, 0.47 mmol) in ethanol (20 mL) was added 10% palladium-on-carbon (100 mg). The reaction mixture was stirred under a hydrogen atmosphere using a balloon filled with hydrogen gas for 2 h at room temperature. The reaction mixture was filtered through Celite and the residue was rinsed with ethanol under a nitrogen atmosphere. The filtrate was used without further purification.
Reaction SMILES: [CH:1]12[CH2:13][CH2:12][CH:8]([CH2:9][NH:10][CH2:11]1)[C:7]1[C:2]2=[CH:3][C:4]([NH:14][C:15]2[N:20]=[C:19]([NH:21][C@@H:22]3[CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]3[NH:28][S:29]([CH3:32])(=[O:31])=[O:30])[C:18]([Cl:33])=[CH:17][N:16]=2)=[CH:5][CH:6]=1.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>>[Cl:33][C:18]1[C:19]([NH:21][C@@H:22]2[CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]2[NH:28][S:29]([CH3:32])(=[O:31])=[O:30])=[N:20][C:15]([NH:14][C:4]2[CH:3]=[C:2]3[C:7](=[CH:6][CH:5]=2)[CH:8]2[CH2:12][CH2:13][CH:1]3[CH2:11][N:10]([S:35]([CH3:34])(=[O:37])=[O:36])[CH2:9]2)=[N:16][CH:17]=1
Reactant: CS(=O)(=O)Cl
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Nc2ccc3c(c2)C2CCC3CNC2)ncc1Cl
Product: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Nc2ccc3c(c2)C2CCC3CN(S(C)(=O)=O)C2)ncc1Cl

Procedure:
N-{(1R,2R)-2-[5-Chloro-2-(10-methanesulfonyl-10-aza-tricyclo[6.3.2.0*2,7*]trideca-2,4,6-trien-4-ylamino)-pyrimidin-4-ylamino]-cyclohexyl}-methanesulfonamide was prepared from N-{(1R,2R)-2-[2-(10-aza-tricyclo[6.3.2.0*2,7*]trideca-2,4,6-trien-4-ylamino)-5-chloro-pyrimidin-4-ylamino]-cyclohexyl}-methanesulfonamide and methanesulfonyl chloride in an analogous manner to Example 278. Product isolated as a white foam as a mixture of diastereomers (14.79 mg, 42%). LCMS (m/e) 569 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 7.94 (s, 1H), 7.43-7.23 (m, 2H), 7.12-7.06 (m, 1H), 6.91-6.84 (m, 1H), 3.91-3.77 (m, 3H), 3.30-2.96 (m, 5H), 2.79 and 2.77 (diastereomeric singlets, 3H), 2.55 and 2.52 (diastereomeric singlets, 3H), 2.30-2.13 (m, 4H), 1.95-1.70 (m, 4H), 1.45-1.28 (m, 4H).