Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]2[S:9][CH:8]=[N:7][C:6]=2[CH:5]=[C:4]([CH3:11])[C:3]=1[OH:12].[Cl:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:2]2[C:10]3[S:9][CH:8]=[N:7][C:6]=3[CH:5]=[C:4]([CH3:11])[C:3]=2[OH:12])=[CH:16][CH:15]=1
Reactant: Cc1cc2ncsc2c(Br)c1O
Reactant: OB(O)c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: Cc1cc2ncsc2c(-c2ccc(Cl)cc2)c1O
Temperature: 110 °C

Procedure:
The reaction mixture of 7-bromo-5-methylbenzo[d]thiazol-6-ol (5D) (90 mg, 0.37 mmol), 4-chlorophenyl boronic acid (86 mg, 0.55 mmol), Pd(PPh3)4 (40 mg, 0.037 mmol), K2CO3 (153 mg, 1.11 mmol) in 1,2-dimethoxyethane (1 ml)/H2O(0.5 ml) was heated at 110° C. in the microwave for 10 min. Then the reaction mixture was diluted with water, extracted with ethyl acetate. The organic layer was dried over MgSO4, filtered, concentrated and purified by silica gel column (0-100% ethyl acetate/hexanes). LCMS-ESI+: calc'd for C14H10ClNOS: 276.0 (M+H+). Found: 276.2 (M+H+).
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl[C:29]([O:31][CH3:32])=[O:30]>C(Cl)Cl>[CH3:32][O:31][C:29]([N:20]=[C:16]([N:7]1[CH2:6][C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=2[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[CH2:8]1)[O:17][CH2:18][CH3:19])=[O:30]
Reactant: COC(=O)Cl
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=NC(=O)OC)N1Cc2ccccc2-c2ccccc2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.66 g of ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate are placed in 15 ml of methylene chloride with 1 g of triethylamine. 0.95 g of methyl chloroformate is added dropwise while cooling with an ice bath. The mixture is then left to stir at room temperature for 2 hours. The reaction mixture is poured on to ice-water and extracted twice with methylene chloride. The extracts are washed with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The oily residue is chromatographed on silica gel with n-hexane-ethyl acetate (1:1) as the eluent, and there is obtained ethyl N-methoxycarbonyl-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as an oil, mass spectrum m/e: M+ 324 (6), 295 (20), 263 (70), 194 (100), 178 (35), 165 (49).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[Li]CCCC.Br[CH2:17][CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=1[Cl:27].[NH4+].[Cl-]>C1COCC1>[Cl:27][C:21]1[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:20]=1[O:19][CH2:18][CH2:17][CH:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][C:2]1=[O:10]
Reactant: O=C1Cc2ccccc2N1
Reactant: Clc1ccc(OCCBr)c(Cl)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C1Nc2ccccc2C1CCOc1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 4914.3 %

Procedure:
To a suspension of 1,3-dihydroindol-2-one (13.3 g, 0.10 mol) in THF (350 mL) was added dropwise n-BuLi (2.5 M in hexane, 84.0 mL, 0.21 mol) at 0° C. under nitrogen atmosphere. After stirring for 1 h at 0° C., the reaction mixture was cooled to −70° C. and a solution of 1-(2-bromo-ethoxy)-2,4-dichlorobenzene (32.4 g, 0.12 mmol) in THF (100 mL) was added dropwise. The mixture was stirred overnight at r.t and poured into NH4Cl(aq. sat.). The separated aqueous layer was extracted with EtOAc three times. The combined extracts were washed with water, dried and evaporated. The crude product was purified by silica gel chromatography first and then purified by prep HPLC to give 3-[2-(2,4-dichlorophenoxy)-ethyl]-1,3-dihydroindol-2-one (1.9 g, 5.8% yield) as an off-white solid. 1H NMR (DMSO-d6) δ: 10.38 (s, 1 H), 7.54 (d, 1 H, J=2.4 Hz), 7.35 (dd, 1 H, J1=8.8 Hz, J2=2.4 Hz), 7.28 (1 H, J=7.2 Hz), 7.17-7.13 (m, 2 H), 6.92 (t, 1 H, J=7.2 Hz), 6.81 (d, 1 H, J=7.6 Hz), 4.24-4.20 (m, 2 H), 3.59 (t, 1 H, J=6.8 Hz), 2.29-2.19 (m, 2 H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:30])[NH:8][C:9]2[C:14]([C:15]=1[N:16]1[CH2:21][CH2:20][N:19]([C:22]([C:24]3[S:25][CH:26]=[CH:27][CH:28]=3)=[O:23])[CH2:18][CH2:17]1)=[CH:13][C:12]([F:29])=[CH:11][N:10]=2)=[O:5])[CH3:2].[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:30])[N:8]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:9]2[C:14]([C:15]=1[N:16]1[CH2:21][CH2:20][N:19]([C:22]([C:24]3[S:25][CH:26]=[CH:27][CH:28]=3)=[O:23])[CH2:18][CH2:17]1)=[CH:13][C:12]([F:29])=[CH:11][N:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(N2CCN(C(=O)c3cccs3)CC2)c2cc(F)cnc2[nH]c1=O
Reactant: BrCc1ccccc1
Product: CCOC(=O)c1c(N2CCN(C(=O)c3cccs3)CC2)c2cc(F)cnc2n(Cc2ccccc2)c1=O

Procedure:
This compound was prepared from 6-fluoro-2-oxo-4-[4-(thiophene-2-carbonyl)-piperazin-1-yl]-1,2-dihydro-[1,8]-naphthyridine-3-carboxylic acid ethyl ester (80) and benzyl bromide according to General Procedure B. Yield 152 mg (21%), MP 130° C.; 1H-NMR (DMSO-d6): δ 1.28 (t, J=7.2 Hz, 3H), 3.15 (m, 4H), 3.90 (m, 4H), 4.32 (q, J=7.2 Hz, 2H), 5.55 (s, 2H), 7.14-7.30 (m, 6H), 7.45 (d, J=3.6 Hz, 1H), 7.80 (d, J=4.8 Hz, 1H), 8.16 (dd, J=2.8, 8.8 Hz, 1H), 8.74 (d, J=2.8 Hz, 1H); EIMS: 521 (M+1). Anal. (C27H25FN4O4S) C, H. N.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][C:6]1=[O:10].[Br:11][C:12]1[C:17]([CH3:18])=[CH:16][C:15](O)=[CH:14][C:13]=1[CH3:20]>>[Br:11][C:12]1[C:17]([CH3:18])=[CH:16][C:15]([O:1][CH2:2][CH2:3][CH2:4][N:5]2[CH2:9][CH2:8][CH2:7][C:6]2=[O:10])=[CH:14][C:13]=1[CH3:20]
Reactant: O=C1CCCN1CCCO
Reactant: Cc1cc(O)cc(C)c1Br
Product: Cc1cc(OCCCN2CCCC2=O)cc(C)c1Br

Procedure:
According to the method of (Example 36) <Step 7>, from 1-(3-hydroxypropyl)pyrrolidin-2-one (3.8 mL) and 4-bromo-3,5-dimethylphenol (5.0 g), a crude product (14.6 g) containing the subject compound was obtained.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6]([C:10]([F:13])([F:12])[F:11])=[CH:5][N:4]=1.[CH2:14]([S:16][C:17]1[C:22]([C:23](O)=[O:24])=[CH:21][N:20]=[C:19]([C:26]([F:29])([F:28])[F:27])[CH:18]=1)[CH3:15].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>O.N1C=CC=CC=1>[CH3:1][NH:2][C:3]1[C:8]([NH:9][C:23]([C:22]2[CH:21]=[N:20][C:19]([C:26]([F:28])([F:29])[F:27])=[CH:18][C:17]=2[S:16][CH2:14][CH3:15])=[O:24])=[CH:7][C:6]([C:10]([F:13])([F:11])[F:12])=[CH:5][N:4]=1
Reactant: CCSc1cc(C(F)(F)F)ncc1C(=O)O
Reactant: CNc1ncc(C(F)(F)F)cc1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: c1ccncc1
Product: CCSc1cc(C(F)(F)F)ncc1C(=O)Nc1cc(C(F)(F)F)cnc1NC
Temperature: 25 °C
Reaction time: 5 h
Yield: 82.8 %

Procedure:
A mixture of 428 mg of N2-methyl-5-trifluoromethylpyridine-2,3-diamine, 562 mg of 4-ethylsulfanyl-6-trifluoromethylnicotinic acid, 645 mg of EDCI hydrochloride, 30 mg of HOBt and 2.5 ml of pyridine was stirred at room temperature for 5 hours, then allowed to stand at room temperature overnight. Water was poured to the reaction mixture, and the precipitated solid was filtered. The resulting solid was washed with water and n-hexane and then dried to obtain 786 mg of 4-ethylsulfanyl-6-trifluoromethylpyridine-3-carboxylic acid (2-methylamino-5-trifluoromethylpyridin-3-yl)-amide. 4-Ethylsulfanyl-6-trifluoromethylpyridine-3-carboxylic acid (2-methylamino-5-trifluoromethylpyridin-3-yl)-amide
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]3[N:14]=[C:15]([NH:17][C:18]([CH:20]4[CH2:22][CH2:21]4)=[O:19])[N:16]=[C:12]3[CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH2:29]([S:31](Cl)(=[O:33])=[O:32])[CH3:30]>ClCCl>[CH2:29]([S:31]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]3[N:14]=[C:15]([NH:17][C:18]([CH:20]4[CH2:21][CH2:22]4)=[O:19])[N:16]=[C:12]3[CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1)(=[O:33])=[O:32])[CH3:30]
Reactant: CCS(=O)(=O)Cl
Reactant: Nc1ccc(-c2cccc3nc(NC(=O)C4CC4)nn23)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCS(=O)(=O)Nc1ccc(-c2cccc3nc(NC(=O)C4CC4)nn23)cc1
Reaction time: 4 h

Procedure:
Cyclopropanecarboxylic acid [5-(4-amino-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amide (0.05, 0.17 mmol) was suspended in dichloromethane (2 mL). Pyridine (0.027 mL, 0.34 mmol) and ethanesulfonyl chloride (0.019 mL, 0.204 mmol) were added and the mixture was stirred for 4 hours. A further equivalent of pyridine and ethanesulfonyl chloride were added and the mixture was stirred overnight. The volatiles were removed in vacuo and the crude product was purified by preparatory HPLC. LCMS method: 2, RT: 3.11 min, MI: 386 [M+1]. NMR (1H, DMSO, 300 MHz): 0.82 (d, 4H), 1.24 (t, 3H), 2.01 (brs, 1H), 3.20 (q, 2H), 7.27 (dd, 1H), 7.36 (d, 2H), 7.68 (m, 2H), 8.02 (d, 2H), 9.98 (brs, 1H), 11.15 (s, 1H).
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26]([OH:28])=O)[CH2:10]2)=[O:8])[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.O[N:63]=[C:64]([O:66][CH:67]([CH3:69])[CH3:68])[NH2:65]>CN(C=O)C>[CH:67]([O:66][C:64]1[N:65]=[C:26]([CH:11]2[CH2:12][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:14][N:9]([C:7]([N:1]3[CH2:2][CH2:3][S:4][CH2:5][CH2:6]3)=[O:8])[CH2:10]2)[O:28][N:63]=1)([CH3:69])[CH3:68]
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCSCC2)C1
Reactant: CC(C)OC(N)=NO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)Oc1noc(C2CC(c3ccc(OC(F)(F)F)cc3)CN(C(=O)N3CCSCC3)C2)n1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
To a solution of 500 mg (1.20 mmol) of the carboxylic acid from Example 9A in 15.0 ml of DMF were added, at RT, 545 mg (1.43 mmol) of HATU and 0.46 ml (2.63 mmol) of N,N′-diisopropylethylamine, and the mixture was stirred for 30 min. Subsequently, the mixture was admixed with 565 mg (3.56 mmol; 75% purity) of isopropyl N′-hydroxyimidocarbamate [G. Zinner, G. Nebel, Arch. Pharm. 1970, 303, 385-390] and then stirred at RT for 2 h and at 120° C. for 2 h. The reaction solution was concentrated under reduced pressure and purified directly by means of preparative HPLC. Yield: 344 mg (58% of theory)
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH:9]2[C:13]3=[C:14]([F:22])[CH:15]=[N:16][C:17]4[CH:18]=[CH:19][C:20](=[O:21])[N:11]([C:12]=43)[CH2:10]2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[Br:30][C:31]1[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=1.C(=O)(O)[O-].[Na+]>ClCCl>[Br:30][C:31]1[CH:39]=[CH:38][C:34]([C:35]([NH:1][CH:2]2[CH2:7][CH2:6][N:5]([CH2:8][C@@H:9]3[C:13]4=[C:14]([F:22])[CH:15]=[N:16][C:17]5[CH:18]=[CH:19][C:20](=[O:21])[N:11]([C:12]=54)[CH2:10]3)[CH2:4][CH2:3]2)=[O:36])=[CH:33][CH:32]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: NC1CCN(CC2Cn3c(=O)ccc4ncc(F)c2c43)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC1CCN(C[C@H]2Cn3c(=O)ccc4ncc(F)c2c43)CC1)c1ccc(Br)cc1
Yield: 87 %

Procedure:
A solution of 4-[(4-amino-1-piperidinyl)methyl]-3-fluoro-4,5-dihydro-7H-pyrrolo[3,2,1-de]-1,5-naphthyridin-7-one Enantiomer 2 (200 mg, 0.664 mmol) in dichloromethane (5 ml) was treated with triethylamine (0.139 ml, 1 mmol), ice-cooled under argon and treated with 4-bromobenzoyl chloride (150 mg, 0.682 mmol). The solution was shaken with excess aqueous sodium bicarbonate solution, separated and the aqueous re-extracted twice with 15% methanol/dichloromethane. The combined organic extracts were dried and evaporated and the residue chromatographed using dichloromethane/methanol/0.88 ammonia 96:4:0.4 to give 4-bromo-N-(1-{[(4S)-3-fluoro-7-oxo-4,5-dihydro-7H-pyrrolo[3,2,1-de]-1,5-naphthyridin-4-yl]methyl}-4-piperidinyl)benzamide (280 mg, 87%).
Reaction SMILES: CC1(C)[O:10][C:9]2[CH:8]=[CH:7][C:6]([C@H:11]3[O:15]C(C4C=CC=CC=4)=[N:13][C@@H:12]3[C:22]([O:24]C)=[O:23])=[CH:5][C:4]=2[O:3]1>Cl>[CH:7]1[C:6]([C@@H:11]([OH:15])[C@H:12]([NH2:13])[C:22]([OH:24])=[O:23])=[CH:5][C:4]([OH:3])=[C:9]([OH:10])[CH:8]=1
Reactant: COC(=O)[C@H]1N=C(c2ccccc2)O[C@@H]1c1ccc2c(c1)OC(C)(C)O2
Agent: Cl
Product: N[C@H](C(=O)O)[C@H](O)c1ccc(O)c(O)c1
Temperature: 25 °C
Yield: 87.9 %

Procedure:
Methyl (4S,5R)-5-[3, 4-(dimethylmethylenedioxy)phenyl]-2-phenyl-2-oxazoline-4-carboxylate (500 mg, 1.41 mmol) was added to 2N-hydrochloric acid (10 ml) with stirring at room temperature, and the mixture was then refluxed for 16 hours. After cooling to room temperature, about 25° C., the reaction mixture was concentrated under reduced pressure and neutralized with an aqueous 1N-sodium hydroxide solution to obtain a precipitated crystal. The precipitated crystal then was filtered to obtain 265 mg (1.24 mmol, yield: 88%) of L-threo DOPS.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[C:5]([Cl:20])=[CH:4][N:3]=1.[NH2:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25][OH:26].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[Cl:20][C:5]1[C:6]([NH:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)=[N:7][C:2]([NH:21][C:22]2[CH:23]=[C:24]([CH2:25][OH:26])[CH:27]=[CH:28][CH:29]=2)=[N:3][CH:4]=1
Reactant: COc1cccc(CCCNc2nc(Cl)ncc2Cl)c1
Reactant: Nc1cccc(CO)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Solvent: O
Product: COc1cccc(CCCNc2nc(Nc3cccc(CO)c3)ncc2Cl)c1
Temperature: 100 °C
Yield: 80.9 %

Procedure:
To a solution of 2,5-dichloro-N-[3-(3-methoxyphenyl)propyl]pyrimidin-4-amine (0.70 g, 2.2 mmol) and 3-aminobenzyl alcohol (0.38 g, 3.0 mmol) in 1,4-dioxane (19.1 mL) was added p-toluenesulfonic acid monohydrate (0.16 g, 0.82 mmol). The mixture was heated at 100° C. for 16 hours and the reaction was complete. After cooling, the mixture was filtered under vacuum. The cake was washed with cold EtOAc and then H2O to give the desired product as an off-white powder (0.71 g, 79%). LCMS for C21H24ClN4O2 (M+H)+: m/z=399.1.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[N:13]([CH2:16][CH3:17])[N:14]=[CH:15][C:3]=12.C(N(CC)CC)C.[NH2:25][CH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>C(O)C>[CH2:16]([N:13]1[C:4]2=[N:5][CH:6]=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:2]([NH:25][CH:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[C:3]2[CH:15]=[N:14]1)[CH3:17]
Reactant: NC1CCOCC1
Reactant: CCOC(=O)c1cnc2c(cnn2CC)c1Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cnc2c(cnn2CC)c1NC1CCOCC1
Temperature: 80 °C
Yield: 83.7 %

Procedure:
Intermediate 1 (0.20 g) and triethylamine (0.55 ml) were suspended in ethanol (8 ml) and 4-aminotetrahydropyran (Intermediate 21, 0.088 g) was added. The mixture was stirred under nitrogen, heated at 80° C. for 16 h, then concentrated in vacuo. The residue was partitioned between DCM and water. The layers were separated and the organic layer was loaded directly onto an SPE cartridge (silica, 5 g) which was eluted sequentially witI; (i) DCM, (ii) DCM:Et2O (2:1), (iii) DCM:Et2O (1:1), (iv) Et2O and (v) EtOAc. Fractions containing desired material were combined and concentrated in vacuo to afford Intermediate 16 (0.21 g). LCMS showed MH+=319; TRET=2.93 min.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]([OH:13])[CH:10]=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C(=O)N([Br:21])C(=O)C1>C(O)(=O)C>[Br:21][C:10]1[C:11]([OH:13])=[N:12][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][CH:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Oc1ccnc(-c2ccccc2)n1
Solvent: CC(=O)O
Product: Oc1nc(-c2ccccc2)ncc1Br
Temperature: 60 °C
Yield: 75.5 %

Procedure:
To a solution of 2-phenylpyrimidin-4-ol (1.0 g, 5.8 mmol, 1 eq) in acetic acid (20 mL) was added NBS (1.0 g, 5.8 mmol, 1 eq) and heated at 60° C. for 1 h. The reaction solution was concentrated in vacuo and the residue was purified by silica gel chromatography (CH2Cl2/MeOH=97/3 as eluant) to obtain 5-bromo-2-phenylpyrimidin-4-ol (1.1 g, 75.8%) as a white solid. LC-MS (m/z): 251.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 7.35-7.51 (m, 3H), 8.10-8.18 (m, 2H), 8.46 (s, 1H), 13.32 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.C(=O)([O-])[O-].[K+].[K+].Br[CH:19]([CH2:29][O:30][CH3:31])[C:20]([NH:22][C:23]([CH3:28])([CH3:27])[C:24]#[C:25][CH3:26])=[O:21]>CN(C)C=O.O>[N:8]1[C:9]2[C:4](=[CH:3][C:2]([O:1][CH:19]([CH2:29][O:30][CH3:31])[C:20]([NH:22][C:23]([CH3:28])([C:24]#[C:25][CH3:26])[CH3:27])=[O:21])=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC#CC(C)(C)NC(=O)C(Br)COC
Reactant: Oc1ccc2ncccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC#CC(C)(C)NC(=O)C(COC)Oc1ccc2ncccc2c1
Temperature: 80 °C
Reaction time: 72 h
Yield: 29.5 %

Procedure:
6-Hydroxyquinoline (0.083 g), anhydrous potassium carbonate (0.087 g) and 2-bromo-N-(4-methylpent-2-yn-4-yl) 3-methoxypropionamide (0.150 g) in dry N,N-dimethylformamide (3 ml) were stirred and heated to 80° C. for 5 hours then stored for 72 hours at ambient temperature. The yellow suspension was diluted with water, extracted with ethyl acetate and the organic phase was separated then washed with water, dried over magnesium sulphate and evaporated under reduced pressure to a gum. The gum was fractionated by chromatography (silica; ethyl acetate:hexane, 3:2 by volume) to give the required product (0.055 g) as a colourless gum.
Reaction SMILES: CN[C:3]([O:5][CH:6]1[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:13][C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2)=O.[CH2:20](O)[CH:21]=[CH:22]C>>[CH:18]1[C:19]2[CH:6]([O:5][CH2:3][CH:20]=[CH:21][CH3:22])[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[O:13][C:14]=2[CH:15]=[CH:16][CH:17]=1
Reactant: CC=CCO
Reactant: CNC(=O)OC1c2ccccc2Oc2ccccc21
Product: CC=CCOC1c2ccccc2Oc2ccccc21

Procedure:
9-(N-Methylcarbamoyloxy)xanthene (6.0 g., 23.5 mmoles) was stirred with 15 ml. of 2-buten -1-ol for 1.5 hours at room temperature, and the mixture was then filtered. The filtrate was evaporated in vacuo, and the residue was dissolved in ice-cold ether and washed twice with ice-cold portions of 10% aqueous acetic acid, water and 5% aqueous sodium bicarbonate solution. After drying over potassium carbonate, the solvent was removed in vacuo, and the resulting oil was distilled to give 2-buten-1-yl 9-xanthenyl ether, b.p. ca. 110°C. at 0.01 mm.
Reaction SMILES: [N+:1]([C:4]1[N:8]([CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:7]([CH3:17])=[N:6][CH:5]=1)([O-:3])=[O:2].[CH3:18][N:19]([CH:21](N(C)C)OC(C)(C)C)[CH3:20]>CN(C)C=O>[N+:1]([C:4]1[N:8]([CH2:9][CH2:10][N:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)[C:7]([CH:17]=[CH:18][N:19]([CH3:21])[CH3:20])=[N:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: Cc1ncc([N+](=O)[O-])n1CCN1CCOCC1
Solvent: CN(C)C=O
Product: CN(C)C=Cc1ncc([N+](=O)[O-])n1CCN1CCOCC1

Procedure:
2.4 g. (0.01 mole) of 5-nitro-2-methyl-1-(2-morpholinoethyl)-imidazole and 2.1 g. (0.012 mole) of bis-dimethylaminotert.-butoxymethane were heated in 9 ml. of dimethylformamide to 130° C. for 60 minutes. After removal of the solvent by evaporation, the residue was crystallized with isopropanol; m.p. 105°-106° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([O:28]S(C)(=O)=O)[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:17][CH:16]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH:33]1[C:38](O)=[CH:37][CH:36]=[C:35]([CH3:40])[CH:34]=1>CN(C)C=O>[CH2:7]([O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([O:28][C:38]2[CH:37]=[CH:36][C:35]([CH3:40])=[CH:34][CH:33]=2)[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:17][CH:16]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Cc1ccc(O)cc1
Reactant: CCOC(=O)C(Cc1ccc(OCc2ccccc2)cc1)OS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1ccc(OCc2ccccc2)cc1)Oc1ccc(C)cc1
Temperature: 70 °C
Reaction time: 16 h
Yield: 27.6 %

Procedure:
Potassium carbonate (8.09 g) was added to a solution of ethyl 3-(4-benzyloxyphenyl)-2-methanesulfonyloxypropionate (11.1 g), which is the product of Reference example 35(a), and p-cresol (2.85 g) in N,N-dimethylformamide (110 ml). This mixture was stirred at 70° C. for 16 hours. The reaction mixture was partitioned between ethyl acetate and water and the layers were separated. The ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified via chromatography on silica gel column using hexane/ethyl acetate=9/1 as the eluant to afford the desired compound (2.84 g) as a colorless oil.
Reaction SMILES: CO[C:3]([C:5]1[C:9]([S:10]([CH3:12])=[O:11])=[C:8]([NH2:13])[N:7]([C:14]2[C:19]([Cl:20])=[CH:18][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:16][C:15]=2[Cl:25])[N:6]=1)=[NH:4].Cl.[O:27]([NH2:29])[CH3:28]>CO>[NH2:13][C:8]1[N:7]([C:14]2[C:15]([Cl:25])=[CH:16][C:17]([C:21]([F:23])([F:24])[F:22])=[CH:18][C:19]=2[Cl:20])[N:6]=[C:5]([C:3](=[NH:4])[NH:29][O:27][CH3:28])[C:9]=1[S:10]([CH3:12])=[O:11]
Reactant: COC(=N)c1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1S(C)=O
Reactant: CON
Agent: Cl
Solvent: CO
Product: CONC(=N)c1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1S(C)=O
Reaction time: 4 h
Yield: 27.2 %

Procedure:
To a stirred solution of 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-methylsulfinyl-1H-pyrazole-3-carboximidic acid methyl ester (1.0 g) in anhydrous methanol was added anhydrous methoxylamine hydrochloride (0.2 g). After 4 hours at 20° C., the mixture was evaporated and dichloromethane and water added. The organic layer was dried (MgSO4), evaporated and chromatographed on a florisil column, eluting with 3:1 dichloromethane/ethyl acetate to give 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-N-methoxy-4-methylsulfinyl-1H-pyrazole-3-carboximidamide(0.28 g), m.p.140-145° C. Compound 49. By proceeding in a similar manner the following compounds were prepared: 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-N-methoxy-4-trifluoromethylsulfinyl-1H-pyrazole-3-carboximidamide, m.p.169-170° C. Compound 41; and 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-N-hydroxy-4-trifluoromethylsulfinyl-1H-pyrazole-3-carboximidamide, m.p.222-224° C. Compound 40.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[CH:2]1.[C:13]1([C:18]2[CH:19]=[CH:20][C:21]3[CH2:22][C@H:23]4[C@@H:28]([C:29]=3[CH:30]=2)[CH2:27][CH2:26][CH2:25][NH:24]4)[CH2:17][CH2:16][CH2:15][CH:14]=1>>[N:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:24]3[CH2:25][CH2:26][CH2:27][C@@H:28]4[C:29]5[CH:30]=[C:18]([C:13]6[CH2:17][CH2:16][CH2:15][CH:14]=6)[CH:19]=[CH:20][C:21]=5[CH2:22][C@H:23]34)=[O:12])=[CH:9][C:4]=2[NH:3][CH:2]=1
Reactant: C1=C(c2ccc3c(c2)[C@H]2CCCN[C@H]2C3)CCC1
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Product: O=C(c1ccc2nc[nH]c2c1)N1CCC[C@@H]2c3cc(C4=CCCC4)ccc3C[C@@H]21
Yield: 49 %

Procedure:
The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and cis-6-cyclopent-1-enyl-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1. Yield: 49% of theory; LC (method 1): tR=2.64 min; Mass spectrum (ESI+): m/z=384 [M+H]+.