Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:22][CH:21]([CH2:23][O:24]S(C)(=O)=O)[O:20]C2=O)=[CH:14][CH:13]=1)=[NH:11])(=[O:8])C1C=CC=CC=1.[O:30]=C1ON=C(C2C=CC(N)=CC=2)N1.O1CC1CO>>[O:30]=[C:1]1[O:8][N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][CH2:22][CH:21]([OH:20])[CH2:23][OH:24])=[CH:14][CH:13]=2)[NH:9]1
Reactant: CS(=O)(=O)OCC1CN(c2ccc(C(=N)NC(=O)c3ccccc3)cc2)C(=O)O1
Reactant: Nc1ccc(-c2noc(=O)[nH]2)cc1
Agent: OCC1CO1
Product: O=c1[nH]c(-c2ccc(NCC(O)CO)cc2)no1

Procedure:
3.0 g of 3-[4-(N-benzoylamidino)phenyl]-5-methanesulfonyloxymethyl-2-oxazolidinone [obtainable by reacting 4-(5-oxo-1,2,4-oxadiazolin-3-yl)aniline with 2,3-epoxypropan-1-ol to give N-[4-(5-oxo-1,2,4-oxadiazolin-3-yl)phenyl]-2,3-dihydroxypropylamine, reacting with diethyl carbonate in the presence of tert-butoxide to give 3-[4-(5-oxo-1,2,4-oxazolin-3-yl)phenyl]-5-hydroxymethyl-2-oxazolidinone, reductive cleavage of the 5-oxo-1,2,4-oxadiazoline group, reacting with benzoyl chloride and subsequently esterifying with methanesulfonyl chloride) dissolved in 10 ml of DMF, are added to a solution of 1.2 g of 4-ethoxycarbonylmethylpiperazine (“A”) in 20 ml of DMF, and the mixture is stirred at room temperature for 60 min. Removal of the solvent and the usual working up result in 3-[4-(N-benzoylamidino)phenyl]-5-(4-ethoxycarbonylmethylpiperazinomethyl)-2-oxazolidinone, m.p. 114°.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2-:14].[Na+].CC1C=CC(C(C)C)=CC=1.Cl>CCOC(C)=O.O>[CH2:1]([C:8]1[CH:13]=[CH:12][N:11]=[C:10]([NH2:14])[CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [NH2-]
Reactant: c1ccc(Cc2ccncc2)cc1
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccc(C(C)C)cc1
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1cc(Cc2ccccc2)ccn1
Temperature: 165 °C
Reaction time: 24 h

Procedure:
A mixture of 4-benzylpyridine (14.1 mL, 88.6 mmol), sodium amide (5.71 g, 146 mmol), and p-cymene (105 mL) was heated to 165° C. After 1 d, the mixture was allowed to cool; water (30 mL) and concentrated hydrochloric acid (30 mL) were sequentially added, the aqueous layer was separated, and the organic layer was extracted with 60 mL of 2N HCl (aq). The aqueous extracts were then combined, washed with ether (50 mL), and made strongly basic with solid potassium hydroxide, during which time a brown oil separated. The oil was extracted into DCM (2×150 mL). The combined extracts were then dried over sodium sulfate, filtered, and concentrated to give a brown oil. Column chromatography (ISCO, 80 g, 50->100% EtOAc/Hex) afforded 4-benzylpyridin-2-amine as a tan solid. MS (ESI) m/z: Calculated: 184.1; Observed: 185 (M++1).
Reaction SMILES: Cl[C:2]1[C:10]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:9][C:5](C(O)=O)=[C:4](C)[CH:3]=1.[C:16](OC)([O:20][CH3:21])([O:18]C)[CH3:17].C1(C)C=CC=CC=1>O1CCOCC1>[CH3:14][S:11]([C:10]1[C:9]([S:11]([CH3:10])(=[O:13])=[O:12])=[CH:5][C:17]([C:16]([O:20][CH3:21])=[O:18])=[C:3]([CH3:4])[CH:2]=1)(=[O:13])=[O:12]
Reactant: COC(C)(OC)OC
Reactant: Cc1cc(Cl)c(S(C)(=O)=O)cc1C(=O)O
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(S(C)(=O)=O)c(S(C)(=O)=O)cc1C
Temperature: 80 °C
Reaction time: 5 h

Procedure:
A solution of 29.5 g of 4-chloro-5-methanesulfonyl-2-methylbenzoic acid and 18.39 g of trimethyl orthoacetate in 100 ml of dioxane was refluxed until the acid had reacted completely. 150 ml of toluene were added, and the solvent was removed to the extent that the mixture still remained stirrable. 150 ml of 1-methyl-2-pyrrolidone (NMP) and 15.8 g of sodium methanesulfinate were subsequently added, and the mixture was stirred at 80° C. for 5 h. After addition of a further 5.3 g of sodium methanesulfinate, the mixture was stirred for 25 h. Conventional work-up gave methyl 4,5-bismethanesulfonyl-2-methylbenzoate.
Reaction SMILES: [OH:1][C:2]1[N:3]=[N:4][C:5]([C:9]([OH:11])=O)=[C:6]([OH:8])[N:7]=1.[NH3:12]>CN(C)C=O>[O:1]=[C:2]1[NH:7][C:6](=[O:8])[C:5]([C:9]([NH2:12])=[O:11])=[N:4][NH:3]1
Reactant: O=C(O)c1nnc(O)nc1O
Reactant: N
Solvent: CN(C)C=O
Product: NC(=O)c1n[nH]c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
In 10 mL of dimethylformamide is suspended (0.5 g of 3,5-dihydroxy-1,2,4-triazine-6-carboxylic acid obtained according to the method described in literature (JP-A-54-79292). Then, 2.06 g of N,N′-carbonyldiimidazole is added thereto, and the resulting solution in stirred at ambient temperature for 6 hours. The reaction mixture is cooled with ice, saturated with gaseous ammonia, and then stirred for 15 minutes at the same temperature as above. The deposited crystals are collected by filtration to obtain 0.37 g of 3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide.
Reaction SMILES: [CH3:1][C:2]([NH2:27])([CH3:26])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=[CH:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[N:11]=2)=[CH:6][CH:5]=1.[CH:28]([C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][C:32]=1[N:38]1[C:42](=[O:43])[CH2:41][S:40]/[C:39]/1=[N:44]\[C:45](=O)[O:46]C1C=CC([N+]([O-])=O)=CC=1)([CH3:30])[CH3:29]>>[CH:28]([C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][C:32]=1[N:38]1[C:42](=[O:43])[CH2:41][S:40]/[C:39]/1=[N:44]\[C:45]([NH:27][C:2]([CH3:1])([CH3:26])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=[CH:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:24])([F:23])[F:25])=[CH:17][CH:16]=3)[N:11]=2)=[CH:6][CH:5]=1)=[O:46])([CH3:30])[CH3:29]
Reactant: Cc1ccc(C(C)C)c(N2C(=O)CS/C2=N\C(=O)Oc2ccc([N+](=O)[O-])cc2)c1
Reactant: CC(C)(N)Cc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Product: Cc1ccc(C(C)C)c(N2C(=O)CS/C2=N\C(=O)NC(C)(C)Cc2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)c1

Procedure:
The title compound was prepared as described in Example 95 using 2-methyl-1-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propan-2-amine (CB28) and (Z)-4-nitrophenyl (3-(2-isopropyl-5-methylphenyl)-4-oxothiazolidin-2-ylidene)carbamate (CA50), purified by flash column chromatography using 0-100% ethyl acetate/B, where B=1:1 dichloromethane/hexanes, as eluent and isolated as a brown oil (0.018 g, 9%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH:18]=[CH:17][C:16](C(OC(C)(C)C)=O)=[CH:15][CH2:14][N:13]2[C:26]([O:28]C(C)(C)C)=[O:27])(=[O:11])=[O:10])=[CH:5][CH:4]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH:18]=[CH:17][CH:16]=[CH:15][CH2:14][N:13]2[C:26]([OH:28])=[O:27])(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(S(=O)(=O)N2C=CC(C(=O)OC(C)(C)C)=CCN2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(S(=O)(=O)N2C=CC=CCN2C(=O)O)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
The t-butyl 1-[(4-methoxyphenyl)sulfonyl]-5-(t-butoxycarbonyl)-diazepine-2-carboxylate (0.45 g, 0.95 mmol) is dissolved in methylene chloride (1.5 mL) and cooled to 0° C. in an ice bath. Trifluroacetic acid (1.5 mL, 19.0 mmol) was added and the resulting mixture was stirred at 0° C. for 3 hours. The reaction mixture is warmed to room temperature and 1 mL of TFA is added. The reaction mixture is again stirred for an additional hour and the mixture is then concentrated down in vacuo. The residue is carried forward without further purification. The product is obtained as a TFA salt.
Reaction SMILES: [F:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2C2CCCCO2)=[C:4]([NH:17][CH:18]([C:20]2[N:21]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:22](=[O:31])[C:23]3[C:28]([CH:29]=2)=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:30])[CH3:19])[N:3]=1.C([O-])(O)=O.[Na+]>Cl.CCO>[F:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([NH:17][C@H:18]([C:20]2[N:21]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:22](=[O:31])[C:23]3[C:28]([CH:29]=2)=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:30])[CH3:19])[N:3]=1.[F:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([NH:17][CH:18]([C:20]2[N:21]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:22](=[O:31])[C:23]3[C:28]([CH:29]=2)=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:30])[CH3:19])[N:3]=1
Reactant: Cc1cccc2cc(C(C)Nc3nc(F)nc4c3ncn4C3CCCCO3)n(-c3ccccc3)c(=O)c12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1cccc2cc(C(C)Nc3nc(F)nc4[nH]cnc34)n(-c3ccccc3)c(=O)c12
Product: Cc1cccc2cc([C@H](C)Nc3nc(F)nc4[nH]cnc34)n(-c3ccccc3)c(=O)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 188.5 %

Procedure:
3-(1-(2-Fluoro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-ylamino)ethyl)-8-methyl-2-phenylisoquinolin-1(2H)-one (compound 5203) (160 mg, 0.32 mmol) was dissolved in HCl/EtOH (3 M, 5 mL) and the resulting mixture was stirred at room temperature for 1 h. The mixture was neutralized with saturated NaHCO3 aqueous solution to pH=7-8, and extracted with CH2Cl2 (50 mL×3). The combined organic layer was washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was recrystallized from ethyl acetate and hexanes. The solid was collected by filtration and dried in vacuo to afford the desired product, 3-(1-(2-fluoro-9H-purin-6-ylamino)ethyl)-8-methyl-2-phenylisoquinolin-1(2H)-one (5204, compound 245 in Table 4) (125 mg, 94% yield) as a white solid.
Reaction SMILES: [CH3:1][C:2](=[CH:6][CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3](=[O:5])[CH3:4].Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>[Zn]>[OH:5][C:3]([CH3:4])([C:2]([CH3:1])=[CH:6][CH:7]=[CH:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)CBr
Reactant: CC(=O)C(C)=CC=Cc1ccccc1
Agent: [Zn]
Product: CCOC(=O)CC(C)(O)C(C)=CC=Cc1ccccc1

Procedure:
Using 8.60 g of 3-methyl-6-phenyl-3,5-hexadien-2-one, 8.0 ml of ethyl bromoacetate and 4.60 g of zinc, the reaction and the purification of the product were carried out according to the method described in Example 1 (a) affording 12.20 g of ethyl 3-hydroxy-3,4-dimethyl-7-phenyl-4,6-heptadienoate.
Reaction SMILES: C1COCC1.[CH3:6][C:7]1[C:12]([C:13](OC)=[O:14])=[CH:11][C:10]([Cl:17])=[CH:9][N:8]=1.[H-].[Li+].[B+3].[H-].[H-].[H-]>O>[Cl:17][C:10]1[CH:11]=[C:12]([CH2:13][OH:14])[C:7]([CH3:6])=[N:8][CH:9]=1
Reactant: COC(=O)c1cc(Cl)cnc1C
Agent: [B+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ncc(Cl)cc1CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.6 %

Procedure:
To a THF (30 mL) solution of 5-chrolo-2-methyl nicotinic acid methyl ester (CAS# 350597-49-8) (1.0 g), boron lithium hydride (0.153 g) was added at 0° C. The reaction solution was agitated at room temperature for 2 hours. The reaction solution was added to iced water and the reaction solution was extracted with ethyl acetate. The obtained organic layer was washed with a saturated salt solution, and it concentrated under reduced pressure after dried over anhydrous magnesium sulfate. 0.26 g of the title compound was obtained by the residue was purified by silica gel chromatography (elution solvent: heptane-ethyl acetate system).
Reaction SMILES: [C:1]([NH2:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:11]([S:13]Cl)=[O:12]>C1(C)C=CC=CC=1>[C:2]1([C:1]2[O:8][C:11](=[O:12])[S:13][N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)c1ccccc1
Reactant: O=C(Cl)SCl
Solvent: Cc1ccccc1
Product: O=c1oc(-c2ccccc2)ns1
Temperature: 100 °C
Reaction time: 4 h
Yield: 79.7 %

Procedure:
To a solution of benzamide (66.03 mmol) in toluene (132 mL) was added chlorocarbonylsulfenyl chloride (82.4 mmol). The reaction mixture was stirred at 100° C. for 4 h. After cooling to r.t. the reaction mixture was concentrated in vacuo, and the residue was crystallized from EtOAc to give the title compound (9.43 g) as a white solid: MS (m/z) 179.1 (M+1).
Reaction SMILES: [F:1][CH2:2][CH:3]([N:6]1[CH2:12][CH2:11][C:10]2[CH:13]=[C:14]([NH2:19])[C:15]([O:17][CH3:18])=[CH:16][C:9]=2[CH2:8][CH2:7]1)[CH2:4][F:5].Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[S:34]([CH:37]([CH3:39])[CH3:38])(=[O:36])=[O:35])[C:24]([Cl:40])=[CH:23][N:22]=1>>[Cl:40][C:24]1[C:25]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[S:34]([CH:37]([CH3:39])[CH3:38])(=[O:36])=[O:35])=[N:26][C:21]([NH:19][C:14]2[C:15]([O:17][CH3:18])=[CH:16][C:9]3[CH2:8][CH2:7][N:6]([CH:3]([CH2:2][F:1])[CH2:4][F:5])[CH2:12][CH2:11][C:10]=3[CH:13]=2)=[N:22][CH:23]=1
Reactant: COc1cc2c(cc1N)CCN(C(CF)CF)CC2
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)C(C)C)n1)CCN(C(CF)CF)CC2

Procedure:
5-Chloro-N(2)-[3-(2-fluoro-1-fluoromethyl-ethyl)-8-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl]-N(4)-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine was prepared from 3-(2-fluoro-1-fluoromethyl-ethyl)-8-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and (2,5-dichloro-pyrimidin-4-yl)-[2-(propane-2-sulfonyl)-phenyl]-amine in an analogous manner to Example 308c. Product isolated as a white foam (95 mg 44%). LCMS (m/e) 580 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 9.52 (s, 1H), 8.57 (d, 1H, J=8.4 Hz), 8.17 (s, 1H), 8.00 (s, 1H), 7.94 (d, 1H, J=7.9 Hz), 7.67-7.58 (m, 1H), 7.50 (s, 1H), 7.32-7.24 (m, 1H), 6.67 (s, 1H), 4.76-4.66 (m, 2H), 4.65-4.55 (m, 2H), 3.89 (s, 3H), 3.33-3.10 (m, 2H), 2.91-2.79 (m, 6H), 2.79-2.69 (m, 2H), 1.35 (s, 3H), 1.33 (s, 3H).
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:4]=1[N:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH3:17])[CH2:12][CH2:11]1.[CH3:18][C:19]1[N:24]=[C:23]([SH:25])[N:22]=[C:21]([OH:26])[CH:20]=1.C(N(CC)CC)C>C(O)C>[Cl:9][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH3:17])[CH2:12][CH2:11]2)[C:3]=1[CH2:2][S:25][C:23]1[N:22]=[C:21]([OH:26])[CH:20]=[C:19]([CH3:18])[N:24]=1
Reactant: CCN1CCN(c2cccc(Cl)c2CBr)CC1
Reactant: Cc1cc(O)nc(S)n1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCN1CCN(c2cccc(Cl)c2CSc2nc(C)cc(O)n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 8.1 %

Procedure:
A mixture of 1-[2-(bromomethyl)-3-chlorophenyl]-4-ethylpiperazine (24.8 mmol), 6-methyl-2-sulfanylpyrimidin-4-ol (2.35 g, 16.5 mmol), and triethylamine (17 mL, 124 mmol) in absolute ethanol (300 mL) was stirred at room temperature overnight. The solid material was removed by filtration. The filtrate was recovered and evaporated. The solid residue was treated with water (500 mL). The mixture was extracted with DCM (3×200 mL) and EtOAc (1×200 mL). The organic extracts were combined, dried over MgSO4, filtered, evaporated, and dried in vacuo. The crude product was purified by flash chromatography (0-20% MeOH/DCM and 0-15% MeOH/DCM), affording 2-({[2-chloro-6-(4-ethylpiperazin-1-yl)phenyl]methyl}sulfanyl)-6-methylpyrimidin-4-ol (505 mg, 5% yield); 1H NMR (400 MHz, DMSO-d6): δ 1.00 (t, 3H, J=7.2 Hz), 2.24 (s, 3H), 2.85 (m, 2H), 2.50 (m, 4H), 2.87 (m, 4H), 4.67 (s, 2H), 6.02 (s, 1H), 7.22 (m, 2H), 7.32 (t, 1H, J=8.0 Hz); M+379.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.Cl[C:13]1[CH:18]=[C:17]([C:19]([OH:22])([CH3:21])[CH3:20])[CH:16]=[C:15]([C:23]([F:26])([F:25])[F:24])[N:14]=1.[H-].[Na+]>O1CCCC1>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([O:11][C:13]3[CH:18]=[C:17]([C:19]([OH:22])([CH3:21])[CH3:20])[CH:16]=[C:15]([C:23]([F:24])([F:26])[F:25])[N:14]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: OC1CCC2(CC1)OCCO2
Reactant: CC(C)(O)c1cc(Cl)nc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(O)c1cc(OC2CCC3(CC2)OCCO3)nc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 60 h

Procedure:
1,4-Dioxaspiro[4.5]decan-8-ol (0.25 g, 1.58 mmol) and 2-[2-chloro-6-(trifluoromethyl)pyridin-4-yl]propan-2-ol (0.2 g, 0.835 mmol) were dissolved in tetrahydrofuran (2 mL) and cooled to 0° C. and a 60% mixture of sodium hydride (70.0 mg, 1.75 mmol) in mineral oil was added and the reaction was stirred for 30 minutes at 0° C. and at 25° C. for 60 hours at which time TLC analysis indicated the presence of some product. The reaction was quenched with water, and was extracted with ethyl acetate and the organic extracts were washed with water, saturated NaCl, dried (MgSO4), and evaporated in vacuo. The residue was purified by LC (pH 2) to give the product. MS (ES): 362 (M+1).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[CH:8]=[C:9]([CH:24]=[CH:25][CH:26]=2)[CH2:10][NH:11][C:12](=[O:23])OC2C=CC([N+]([O-])=O)=CC=2)[O:6][CH2:5][CH2:4][O:3]1.[Cl:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1.C(N(CC)CC)C>ClCCl>[Cl:27][C:28]1[CH:34]=[CH:33][C:31]([NH:32][C:12]([NH:11][CH2:10][C:9]2[CH:24]=[CH:25][CH:26]=[C:7]([C:2]3([CH3:1])[O:3][CH2:4][CH2:5][O:6]3)[CH:8]=2)=[O:23])=[CH:30][CH:29]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: CC1(c2cccc(CNC(=O)Oc3ccc([N+](=O)[O-])cc3)c2)OCCO1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(c2cccc(CNC(=O)Nc3ccc(Cl)cc3)c2)OCCO1
Temperature: 25 °C
Yield: 62 %

Procedure:
4-Nitrophenyl-N-benzylcarbamate 21 (267 mg, 0.767 mmol) was added to a solution of 4-chloroaniline (97 mg, 0.767 mmol) and triethylamine in dichloromethane (5 mL). The mixture was stirred at room temperature until starting materials were consumed. The reaction mixture was then diluted with dichloromethane (50 mL) and washed with aq. NaOH, water and brine. The organic layer was dried over anhydrous MgSO4, filtered and concentrated The residue was purified by column chromatography eluting with methanol/chloroform to give 22 (165 mg, 71%). 1H NMR (CDCl3, 400 MHz) δ 1.58 (s, 3H), 3.71 (t, J=6.8 Hz, 2H), 3.99 (t, J=6.8 Hz, 2H), 4.36 (d, J=5.6 Hz, 2H), 6.78 (s, 1H), 7.16-7.18 (m, 4H), 7.23-7.26 (m, 1H), 7.35 (d, J=5.6 Hz, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:17]=[CH:16][C:7](/[CH:8]=[C:9]2/[C:10](=[O:15])[NH:11][C:12](=[O:14])[S:13]/2)=[CH:6][CH:5]=1)[CH3:2].Br[CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].C(=O)([O-])[O-].[K+].[K+].C(OC1C=CC(/C=C2/C(=O)N(CCC)C(=O)S/2)=CC=1)C>>[CH2:1]([O:3][C:4]1[CH:17]=[CH:16][C:7](/[CH:8]=[C:9]2/[C:10](=[O:15])[N:11]([CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:12](=[O:14])[S:13]/2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(/C=C2\SC(=O)NC2=O)cc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: CCCN1C(=O)S/C(=C\c2ccc(OCC)cc2)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOc1ccc(/C=C2\SC(=O)N(CC(=O)OC(C)(C)C)C2=O)cc1

Procedure:
The title compound 28g was prepared from compound 2 (249 mg, 1.00 mmol), tert-butyl bromoacetate (215 mg, 1.10 mmol) and potassium carbonate (276 mg, 2.00 mmol) in a manner similar to that described for 28d in 99.0% (360 mg) yield as a pale-yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([F:21])[CH:20]=1)[C:5]([C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=1)([OH:9])[C:6]([OH:8])=[O:7].[CH2:22]1CCN2C(=NCCC2)CC1.CI>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([F:21])[CH:20]=1)[C:5]([C:10]1[CH:11]=[C:12]([F:17])[CH:13]=[C:14]([F:16])[CH:15]=1)([OH:9])[C:6]([O:8][CH3:22])=[O:7]
Reactant: O=C(O)C(O)(c1cc(F)cc(F)c1)c1cc(F)cc(F)c1
Reactant: C1CCC2=NCCCN2CC1
Solvent: CI
Solvent: CC#N
Product: COC(=O)C(O)(c1cc(F)cc(F)c1)c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
20.15 g (0.0671 mol) of 3,3′,5,5′-tetrafluorobenzilic acid are placed in 250 ml acetonitrile, 18.6 g (0.121 mol) of DBU, and 34.4 g (0.2426 mol) of methyl iodide is added and then stirred for 6 hours at ambient temperature. The reaction mixture is evaporated to dryness, the residue extracted with ethyl acetate and water, the organic phase dried over MgSO4, evaporated to dryness. The product is recrystallized from cyclohexane. Yield: 15.11 g of beige crystals (68% of theory); melting point: 113° C.-114° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH2:10][O:11][C:12]3[C:13]([F:23])=[C:14]([C:19](=[N:21][OH:22])[NH2:20])[C:15]([F:18])=[CH:16][CH:17]=3)=[N:7][C:6]=2[CH:24]=1.[OH-].[Na+].[CH3:27]OS(OC)(=O)=O.O>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH2:10][O:11][C:12]3[C:13]([F:23])=[C:14]([C:19](=[N:21][O:22][CH3:27])[NH2:20])[C:15]([F:18])=[CH:16][CH:17]=3)=[N:7][C:6]=2[CH:24]=1
Reactant: NC(=NO)c1c(F)ccc(OCc2nc3cc(Cl)ccc3s2)c1F
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CON=C(N)c1c(F)ccc(OCc2nc3cc(Cl)ccc3s2)c1F
Yield: 19 %

Procedure:
A mixture of 3-[(5-chloro-1,3-benzothiazol-2-yl)methoxy]-2,6-difluoro-N′-hydroxybenzenecarboximidamide (222, mg, 0.6 mmol, 1 equiv.), 0.7 N NaOH solution (0.97 ml, 0.68 mmol, 1.13 equiv.) and dimethylsulfate (0.60 ml, 0.63 mmol, 1.05 equiv.) in THF (4 ml) was stirred at 0° C. for 6 h. The mixture was poured into H2O (40 ml) and the precipitant solid was filtered and washed with H2O (2×10 ml) and Et2O (2×10 ml) to give 43 mg (yield 19%) of the desired product. Purity 70% by HPLC (Gemini C18, 50×4.6 mm): m/z 384 [M+H]+, Rt=3.26 min. HPLC-MS analysis suggested also that there was 23% un-reacted starting material and 6% of the N-methylated by-product: 3-[(5-chloro-1,3-benzothiazol-2-yl)methoxy]-2,6-difluoro-N′-hydroxy-N-methylbenzenecarboximidamide.
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:14]=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=3)[N:6]2[N:5]=1)=O.[O:21]=[S:22]1(=[O:36])[CH2:27][CH2:26][N:25]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=2)[CH2:24][CH2:23]1>>[O:36]=[S:22]1(=[O:21])[CH2:23][CH2:24][N:25]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([NH:35][C:4]3[N:9]=[CH:8][C:7]4=[CH:10][CH:11]=[C:12]([C:13]5[CH:14]=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=5)[N:6]4[N:5]=3)=[CH:31][CH:30]=2)[CH2:26][CH2:27]1
Reactant: COc1ccc(-c2ccc3cnc(S(C)=O)nn23)cn1
Reactant: Nc1ccc(CN2CCS(=O)(=O)CC2)cc1
Product: COc1ccc(-c2ccc3cnc(Nc4ccc(CN5CCS(=O)(=O)CC5)cc4)nn23)cn1

Procedure:
[4-(1,1-Dioxo-1$1(6)-thiomorpholin-4-ylmethyl)-phenyl]-[7-(6-methoxy-pyridin-3-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-amine was prepared from 2-methanesulfinyl-7-(6-methoxy-pyridin-3-yl)-pyrrolo[2,1-f][1,2,4]triazine and 4-(1,1-dioxo-1$1(6)-thiomorpholin-4-ylmethyl)-phenylamine in an analogous manner to Example 1049. Product isolated as a yellow foam (10 mg, 6%). LCMS (m/e) 465 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.77 (d, 1H, J=2.1 Hz), 8.72 (s, 1H), 8.40 (dd, 1H, J=8.7 and 2.4 Hz), 7.58 (d, 2H, J=8.4 Hz), 7.26 (d, 2H, J=8.4 Hz), 6.94 (d, 1H, J=4.7 Hz), 6.92-6.84 (m, 2H), 6.82 (s, 1H), 4.04 (s, 3H), 3.62 (s, 2H), 3.10-3.03 (m, 4H), 3.03-2.96 (m, 4H).
Reaction SMILES: [C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([C:21]5[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=5)=[CH:18]4)=[CH:13][C:12]=3[O:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH3:36])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C1(NC2CCCCC2)CCCCC1.S(Cl)([Cl:52])=O>ClCCl>[C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([C:21]5[CH:29]=[CH:28][C:24]([C:25]([Cl:52])=[O:26])=[CH:23][CH:22]=5)=[CH:18]4)=[CH:13][C:12]=3[O:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH3:36])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: O=S(Cl)Cl
Reactant: COCCOCOc1cc2ccc(-c3ccc(C(=O)O)cc3)cc2cc1C12CC3CC(CC(C3)C1)C2
Agent: C1CCC(NC2CCCCC2)CC1
Solvent: ClCCl
Product: COCCOCOc1cc2ccc(-c3ccc(C(=O)Cl)cc3)cc2cc1C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
10 g (20.6 mmol) of 4-[7-(1-adamantyl)-6-methoxyethoxymethoxy-2-naphthyl]benzoic acid and 100 ml of dichloromethane were introduced into a round-bottomed flask and 4.3 ml (21.6 mmol) of dicyclohexylamine were added dropwise. The reaction mixture was stirred at room temperature for one hour and 2.2 ml (21.6 mmol) of thionyl chloride were added dropwise. The reaction mixture was stirred for one hour and was evaporated to dryness, the residue was taken up in ethyl ether, the dicyclohexylamine salt was filtered off and the filtrate was evaporated. 10.4 g (100%) of the crude acid chloride were collected, which acid chloride was used as is in the synthesis to follow.