Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[C:7]#[N:8])([O-])=O.[CH3:15][C:16]1[N:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:15][C:16]1[N:21]=[CH:20][C:19]([O:22][C:4]2[CH:5]=[C:6]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=2)[C:7]#[N:8])=[CH:18][CH:17]=1
Reactant: Cc1ccc(O)cn1
Reactant: N#Cc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(Oc2cc(C#N)cc([N+](=O)[O-])c2)cn1
Temperature: 110 °C
Yield: 73.5 %

Procedure:
3,5-dinitro-benzonitrile (3 g, 16 mmol), 6-methylpyridin-3-ol (1.7 g, 16 mmol), and K2CO3 (4.3 g, 31 mmol) were dissolved in DMF and heated to 110° C. overnight. The reaction mixture was poured into water and the mixture was extracted with EtOAc. The combined organics were washed with brine, dried (Na2SO4), concentrated in vacuo and purified by silica gel chromatography to provide 3-(6-methylpyridin-3-yloxy)-5-nitrobenzonitrile (3 g, 76% yield). 1H NMR (400 MHz, DMSO) δ 8.50 (s, 1H), 8.38 (s, 1H), 8.08 (s, 1H), 8.01 (s, 1H), 7.59-7.56 (d, J=10 Hz, 1H), 7.38-7.36 (d, J=8.4 Hz, 1H), 1.98 (s, 3H); MS (ESI) m/z: 256.3 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([O:12][CH3:13])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:14][CH3:15])[CH:3]=1.[B-](F)(F)(F)[F:17].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.O>C(#N)C>[NH2:1][C:2]1[CH:3]=[C:4]([O:14][CH3:15])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:10]([O:12][CH3:13])[C:11]=1[F:17]
Reactant: F[B-](F)(F)F
Reactant: COC(=O)c1c(OC)cc(N)cc1OC
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Solvent: O
Product: COC(=O)c1c(OC)cc(N)c(F)c1OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 20 %

Procedure:
To a solution of methyl 4-amino-2,6-dimethoxybenzoate (510 mg, 2.42 mmol) in acetonitrile (10 mL) at 0° C. was added Selectfluor® (940 mg, 2.66 mmol). The mixture was stirred 30 minutes at 0° C. then water (10 mL) was added. The reaction was extracted twice with ethyl acetate (30 mL). The organic phases were combined, passed through a hydrophobic frit and the solvent was removed in vacuo. Purification of the residue via silica gel column chromatography (0-100% EtOAc in iso-hexane) gave methyl 4-amino-3-fluoro-2,6-dimethoxybenzoate (114 mg, 20%) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 6.05 (d, J=6.4 Hz, 1H), 3.93 (s, 3H), 3.88 (s, 3H), 3.75 (s, 3H).
Reaction SMILES: C(OC(=O)[NH:7]/[C:8](/[NH:17][C:18]1[CH:23]=[CH:22][N:21]=[C:20]([Cl:24])[CH:19]=1)=[N:9]\C(=O)OC(C)(C)C)(C)(C)C.[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29]>ClCCl>[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29].[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29].[Cl:24][C:20]1[CH:19]=[C:18]([NH:17][C:8]([NH2:9])=[NH:7])[CH:23]=[CH:22][N:21]=1
Reactant: CC(C)(C)OC(=O)/N=C(\NC(=O)OC(C)(C)C)Nc1ccnc(Cl)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N=C(N)Nc1ccnc(Cl)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 110.8 %

Procedure:
To a solution of 43.67 g (0.117 mol) of di-tert-butyl{(Z)-[(2-chloropyridin-4-yl)amino]methylylidene}biscarbamate in dichloromethane (800 ml) at room temperature were added 81.64 ml of trifluoroacetic acid (1.06 mol). The reaction mixture was stirred at room temperature for 2 days, concentrated in vacuo, triturated with 100 ml of pentane, and upon standing crystallized to yield 51.68 g of 1-(2-chloropyridin-4-yl)guanidine bis(trifluoroacetate) (yield=99%).
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3].[H-].[Na+].[Cl:14][C:15]1[S:16][C:17]([CH2:20]Cl)=[CH:18][CH:19]=1>O1CCOCC1>[Cl:14][C:15]1[S:16][C:17]([CH2:20][N:1]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:4](=[O:5])[C:2]2=[O:3])=[CH:18][CH:19]=1
Reactant: O=C1Nc2ccccc2C1=O
Reactant: ClCc1ccc(Cl)s1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C1C(=O)N(Cc2ccc(Cl)s2)c2ccccc21
Reaction time: 0.08 h
Yield: 22.4 %

Procedure:
A solution of isatin (125 mg, 0.85 mmol) in anhydrous dioxane (10 mL) was added dropwise to a solution of sodium hydride (60% dispersion in mineral oil, 24 mg, 0.62 mmol) in anhydrous dioxane (10 mL) at 0° C. under argon. The mixture was allowed to stir for 5 minutes and then 2-chloro-5-(chloromethyl)thiophene (0.12 mL, 1.02 mmol) in dioxane (10 mL) was added dropwise to the resulting mixture. The reaction mixture was heated at reflux under argon for 16 h and concentrated in vacuo. The crude material was purified preparative, TLC using 1:24 methanol in chloroform as the eluent, giving the desired product as a yellow solid (53 mg, 0.19 mmol, 22%). 1H NMR (400 MHz): δ 7.62 (d, J=7.4, 1H), 7.56 (t, J=7.8, 1H), 7.14 (t, J=7.7, 1H), 6.94 (d, J=8.0, 1H), 6.90 (d, J=3.2, 1H), 6.78 (d, J=3.7, 1H), 4.90 (s, 2H).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:18][CH:17]([C:19]([N:21]2[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22]2)=[O:20])[CH2:16]1)=O)(C)(C)C>ClCCl>[NH:15]1[CH2:18][CH:17]([C:19]([N:21]2[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22]2)=[O:20])[CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)N2CC[C@H](O)C2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(C1CNC1)N1CC[C@H](O)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
Trifluoroacetic acid (3 mL) was added to a solution of 3-((S)-3-hydroxypyrrolidine-1-carbonyl)azetidine-1-carboxylic acid tert-butyl ester (460 mg, 1.7 mmol) in dichloromethane (12 mL). The resulting reaction mixture was stirred at RT for 2 h. The solvents were reduced in vacuo. The resulting residue was loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was washed with DCM/MeOH, the desired product was subsequently eluted using a mixture of 2M NH3 in MeOH and DCM to afford Azetidin-3-yl-((S)-3-hydroxypyrrolidin-1-yl)methanone as colourless oil (243 mg, 84%). 1H NMR (400 MHz, DMSO, d6): δ 4.28-4.18 (1 H, m), 3.72-3.17 (10 H, m), 2.11-2.10 (1 H, m), 1.81-1.80 (2 H, m)
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].[H-].[Na+].[CH2:7]([O:9][C:10](=[O:13])[CH2:11]Br)[CH3:8].Cl>C1COCC1>[CH2:7]([O:9][C:10](=[O:13])[CH2:11][O:4][CH2:1][C:2]#[CH:3])[CH3:8]
Reactant: C#CCO
Reactant: CCOC(=O)CBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C#CCOCC(=O)OCC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of prop-2-yn-1-ol (815 g, 14.5 mol) in THF (1 L) is added dropwise to a suspension of NaH (60% content) (500 g) in THF (4 L) at 0° C. under nitrogen atmosphere. The stirring is continued at this temperature for 3 h before a solution of bromo-acetic acid ethylester (2.17 kg, 13.0 mol) in THF (2 L) is added dropwise over 1 h. After addition, the temperature is allowed to warm to RT and the reaction mixture is stirred for another 3 h. HCl (2 M, 8 L) is added into the reaction mixture, the organic layer is isolated and the aqueous layer is extracted with EtOAc (3×5 L). The combined organic layer is washed with brine (2 L), dried over anhydrous Na2SO4 and concentrated in vacuo. The crude oil is distilled to give the desired product. Yield: 1.6 kg. 1H NMR: (CDCl3) δ 4.31 (s, 2H), 4.23 (q, J=7.2 Hz, 2H), 4.19 (s, 2H), 2.47 (t, J=2.4 Hz, 1H), 1.29 (t, J=7.2 Hz, 3H).
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:13][S:14]([CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:22]=1[CH:23]=[CH:24][N:25]2[C:30]1[CH:35]=[CH:34][N:33]=[C:32]([NH:36][CH:37]2[CH2:42][CH2:41][CH:40]([C:43]([OH:45])=O)[CH2:39][CH2:38]2)[N:31]=1)(=[O:16])=[O:15].[CH3:46][N:47]([CH:49]1[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1)[CH3:48]>CN(C=O)C>[CH3:46][N:47]([CH3:48])[CH:49]1[CH2:54][CH2:53][N:52]([C:43]([CH:40]2[CH2:39][CH2:38][CH:37]([NH:36][C:32]3[N:31]=[C:30]([N:25]4[C:26]5[C:22](=[C:21]([O:20][CH2:19][CH2:18][CH2:17][S:14]([CH3:13])(=[O:15])=[O:16])[CH:29]=[CH:28][CH:27]=5)[CH:23]=[CH:24]4)[CH:35]=[CH:34][N:33]=3)[CH2:42][CH2:41]2)=[O:45])[CH2:51][CH2:50]1
Reactant: CN(C)C1CCNCC1
Reactant: CS(=O)(=O)CCCOc1cccc2c1ccn2-c1ccnc(NC2CCC(C(=O)O)CC2)n1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CN(C)C1CCN(C(=O)C2CCC(Nc3nccc(-n4ccc5c(OCCCS(C)(=O)=O)cccc54)n3)CC2)CC1
Temperature: 40 °C
Reaction time: 0.17 h

Procedure:
CDI (7.13 g, 44.0 mmol) was added to a mixture of 4-{4-[4-(3-methanesulfonyl-propoxy)-indol-1-yl]-pyrimidin-2-ylamino}-cyclohexanecarboxylic acid (16.00 g, 33.86 mmol) in dry DMF (100 mL) heated to 40° C. under N2. After stirring for 10 min, 100 mL of DMF was added, heated to 40° C., and stirred for an additional 40 min. N,N-dimethyl-piperidin-4-ylamine (5.00 g, 38.9 mmol) was added and allowed to stir overnight at RT. The reaction mixture was concentrated in vacuo, the residue diluted with EtOAc and washed with cold H2O (4×), 5% NaOH aqueous solution (4×), H2O and brine. The organic layer was dried and the remaining solvent removed in vacuo. The product, (4-dimethylamino-piperidin-1-yl)-(4-{4-[4-(3-methane-sulfonyl-propoxy)-indol-1-yl]-pyrimidin-2-ylamino}-cyclohexyl)-methanone (Compound 275), was crystallized from EtOH/H2O as a white solid (11.9 g, 60.3%). MS M+1 (583), mp 182.4-183° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N+:9]([O-:11])=[O:10].[Cl:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=1[OH:23]>>[Cl:12][C:13]1[CH:18]=[C:17]([C:19]([F:20])([F:21])[F:22])[CH:16]=[CH:15][C:14]=1[O:23][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1c(F)cccc1F
Reactant: Oc1ccc(C(F)(F)F)cc1Cl
Product: O=[N+]([O-])c1c(F)cccc1Oc1ccc(C(F)(F)F)cc1Cl

Procedure:
This material was prepared in 47% yeild from 2,6-difluoronitrobenzene and 2-chloro-4-trifluoromethylphenol following the general procedure outlined in Example 88. The product was isolated as an oil which was characterized by IR and 1H NMR spectroscopy.
Reaction SMILES: [F:1][C:2]([F:16])([S:13]([OH:15])=[O:14])[C:3]([F:12])([F:11])[C:4]([F:10])([F:9])[C:5]([F:8])([F:7])[F:6].[CH2:17]=[CH:18][C:19](=[CH2:21])[CH3:20].C([O-])(O)=O.[Na+]>>[CH3:20][C:19]([CH3:21])=[CH:18][CH2:17][S:13]([C:2]([F:1])([F:16])[C:3]([F:11])([F:12])[C:4]([F:10])([F:9])[C:5]([F:8])([F:7])[F:6])(=[O:15])=[O:14]
Reactant: O=S(O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: C=CC(=C)C
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(C)=CCS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 0 °C
Yield: 60 %

Procedure:
25 g (0.088 mol) of perfluorobutanesulphinic acid were initially introduced into a 100 ml three-necked flask and cooled to 0° C. Freshly distilled isoprene was then added dropwise, in excess, during which a dropping rate of 1 drop per minute had to be maintained. After the dropwise addition, the solution was immediately poured into ice-water neutralized with NaHCO3 and extracted with ether. After drying with MgSO4, the ether extract was filtered, the ether was stripped off from the filtrate in a rotary evaporator and the residue was distilled. Perfluorobutyl 3-methyl-2-butenyl sulphone of boiling point 41° C./0.1 mm Hg was obtained as a yellowish-tinged liquid in a yield of 60 to 70% of theory.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[C:14]([C:16]([NH2:18])=[O:17])[CH:15]=2)[NH:12][CH:11]=[C:10]3[CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[Cl:32][CH2:33][CH2:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl>[Cl:32][CH2:33][CH2:34][S:35]([N:22]1[CH2:23][CH2:24][CH:19]([C:10]2[C:9]3[C:13](=[C:14]([C:16]([NH2:18])=[O:17])[CH:15]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:8]=3)[NH:12][CH:11]=2)[CH2:20][CH2:21]1)(=[O:37])=[O:36]
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCNCC3)c[nH]c12
Reactant: O=S(=O)(Cl)CCCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCN(S(=O)(=O)CCCl)CC3)c[nH]c12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 29.2 %

Procedure:
To a solution of 5-phenyl-3-(4-piperidinyl)-1H-indole-7-carboxamide (65 mg, 0.2 mmol) in CH2Cl2 (5 mL) at 0° C., triethylamine (0.11 mL, 0.8 mmol) and 2-chloroethanesulfonyl chloride (0.042 mL, 0.4 mmol) were added. After stirring at 0° C. for 30 min. the reaction mixture was partitioned between CH2Cl2 and water. The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (2×). The combined organic phase was dried over magnesium sulfate and the solvent removed under reduced pressure. The resulting residue was purified by filtration through an SPE Cartridge (Aminopropyl NH2, 500 mg/6 mL) to give the desired product (26 mg, 32%).
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][C:3]=1[O:18][CH3:19].Br[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>>[CH3:19][O:18][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[C:7]([O:8][CH3:9])[C:2]=1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH3:21]
Reactant: CCCCCCCCCCCCCCBr
Reactant: COc1cc(C=Cc2ccccc2)cc(OC)c1Br
Product: CCCCCCCCCCCCCCc1c(OC)cc(C=Cc2ccccc2)cc1OC

Procedure:
This material was prepared from 2-bromo-1,3-dimethoxy-5-(2-phenylethenyl)benzene and 1-bromo-n-tetradecane by the same procedure as described in example 15. 1HNMR (CDCl3, ppm): δ 0.91 (m, 6H), 1.29 (m, 22H), 2.65 (m, 2H), 3.90 (s, 6H), 6.73 (s, 2H), 7.10 (s, 2H), 7.26 (m, 1H), 7.36 (m, 2H), 7.52 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([CH2:15][CH3:16])([CH2:13][CH3:14])[C:6]=2[CH:17]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1I>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1[NH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([CH2:15][CH3:16])([CH2:13][CH3:14])[C:6]=2[CH:17]=1
Reactant: Clc1ccc(Cl)c(I)c1
Reactant: CCC1(CC)OC(=O)N(C)c2ccc(N)cc21
Product: CCC1(CC)OC(=O)N(C)c2ccc(Nc3cc(Cl)ccc3Cl)cc21

Procedure:
Prepared from 6-amino-4,4-diethyl-1-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one and 1,4-dichloro-2-iodobenzene according to the coupling procedure described in example 2. 1H NMR (DMSO-d6): δ 7.85 (s, 1H), 7.41 (d, J=8.5 Hz, 1H), 7.20 (dd, J=8.7, 2.4 Hz, 1H), 7.09 (m, 2H), 6.89 (d, J=2.4 Hz, 1H), 6.83 (dd, J=8.5, 2.4 Hz, 1H), 3.29 (s, 3H), 1.97 (m, 4H), 0.82 (t, J=7.3 Hz, 6H); MS (ESI) m/z [M+H]+ (379/381/383); Anal. calcd for C19H20Cl2N2O2: C, 60.17; H, 5.32; N, 7.39. Found: C, 59.11; H, 5.36; N, 6.84.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])=[CH:4][CH:3]=1.C([O-])([O-])O[CH2:18][CH3:19]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:18][CH3:19])[S:9]([C:12]([F:15])([F:13])[F:14])(=[O:11])=[O:10])=[CH:6][CH:7]=1
Reactant: CCOC([O-])[O-]
Reactant: O=S(=O)(Nc1ccc(Br)cc1)C(F)(F)F
Product: CCN(c1ccc(Br)cc1)S(=O)(=O)C(F)(F)F
Yield: 93 %

Procedure:
A solution of 1.52 g (5 mmol) of N-(4-bromophenyl)-C,C,C-trifluoro-methanesulphonamide (Example 13bv)) in 25 ml of ethyl orthoformate was heated to reflux for 6 hours. Subsequently, the readily volatile constituents were distilled off on a water-jet vacuum and the residue was chromatographed over a flash column with hexane/ethyl acetate 95:5. There were obtained 1.55 g (93%) of N-(4-bromophenyl)-N-ethyl-C,C,C- trifluoro-methanesulphonamide as a pale yellow oil. MS (EI): 331 and 333 (M+, 44%), 198 and 200 ([M-SO2 CF3 ]+, 80%), 118 ([M-(SO2CF3 +HBr)]+, 100%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:28])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][NH:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:29][O:30][C:31](=[O:41])[C:32]1[CH:37]=[CH:36][C:35]([N:38]=[C:39]=[O:40])=[CH:34][CH:33]=1>C(Cl)Cl>[CH3:29][O:30][C:31](=[O:41])[C:32]1[CH:33]=[CH:34][C:35]([NH:38][C:39]([N:9]2[CH2:10][C@@H:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[C@@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:8]2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[F:28])=[O:40])=[CH:36][CH:37]=1
Reactant: CC(C)(C)CC1CNC(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: COC(=O)c1ccc(N=C=O)cc1
Solvent: ClCCl
Product: COC(=O)c1ccc(NC(=O)N2C[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.7 %

Procedure:
A mixture of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (84.6 mg, 0.20 mmol) and 4-isocyanato-benzoic acid methyl ester (Aldrich, 53.1 mg, 0.30 mmol) in CH2Cl2 (2 mL) was stirred at rt for 1 h. The reaction mixture was then concentrated and purified by flash column to give rac 4-{[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]-amino}-benzoic acid methyl ester (89.7 mg, 74.7%) which was used in the next step without further purification.
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[F:23][C:24]1[CH:25]=[C:26]([N:30]([CH3:39])[C:31]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)=O)[CH:27]=[CH:28][CH:29]=1>C1(C)C=CC=CC=1>[F:23][C:24]1[CH:25]=[C:26]([N:30]([CH3:39])[C:31]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)=[S:10])[CH:27]=[CH:28][CH:29]=1
Reactant: CN(C(=O)c1ccccn1)c1cccc(F)c1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CN(C(=S)c1ccccn1)c1cccc(F)c1

Procedure:
Lawesson's reagent (3.20 g, 7.9 mmol) and N-(3-fluorophenyl)-N-methyl-2-pyridinecarboxamide (3.51 g, 15.2 mmol) were heated to reflux in toluene (45 mL) under nitrogen for 2 hours. The residue, after evaporation of the solvent, was dissolved in dichloromethane, preadsorbed onto silica gel, and flash chromatographed (250 g of silica gel eluted with 10% ethyl acetate in petroleum ether) to yield N-(3-fluorophenyl)-N-methyl-2-pyridinecarbothioamide, as a yellow solid (1.70 g, 45%), m.p. 100°-103° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([N:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.[CH2:26]([N:28]=[C:29]=[O:30])[CH3:27]>C(Cl)(Cl)Cl>[Br:1][C:2]1[C:3]([N:20]2[CH2:21][CH2:22][N:23]([C:29]([NH:28][CH2:26][CH3:27])=[O:30])[CH2:24][CH2:25]2)=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([N:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CN(C)c1ccc(-c2nc3c(N4CCNCC4)c(Br)cnc3[nH]2)cc1
Reactant: CCN=C=O
Solvent: ClC(Cl)Cl
Product: CCNC(=O)N1CCN(c2c(Br)cnc3[nH]c(-c4ccc(N(C)C)cc4)nc23)CC1
Yield: 55 %

Procedure:
This was prepared from [4-(6-bromo-7-piperazin-1-yl-3H-imidazo[4,5-b]pyridin-2-yl)-phenyl]-dimethyl-amine (20 mg, 0.050 mmol), using CHCl3 (1.5 mL) and ethyl isocyanate (1.1 eq, 0.055 mmol, 43 μL). Filtration of the precipitate after 16 h gave the product (13 mg, 56%) as a pale yellow solid; 1H-NMR (500 MHz, DMSO-d6) 1.05 (t, J=7.1 Hz, 3H, CH2CH3), 3.00 (s, 6H, N(CH3)2), 3.09 (qd, J=7.1, 5.4 Hz, 2H, NHCH2), 3.50-3.52 (m, 4H, piperazine N(CH2)2), 3.55-3.57 (4H, m, piperazine N(CH2)2), 6.55 (t, J=5.4 Hz, 1H, NHCH2), 6.82 (d, J=9.0 Hz, 2H, N,N-dimethylaminophenyl), 8.01 (d, J=9.0 Hz, 2H, N,N-dimethylaminophenyl), 8.17 (s, 1H, imidazo[4,5-b]pyridine H-5), 13.18 (s, br, 1H, imidazo[4,5-b]pyridine NH);
Reaction SMILES: CN.[C:3]([O:6][C:7]1[C:8](=[CH:10][CH:11]=[CH:12][CH:13]=1)[OH:9])(=O)[OH:4].[CH2:14]([N:16](CC)CC)C.Cl>C(Cl)Cl>[CH3:14][NH:16][C:3]([O:6][C:7]1[C:8](=[CH:10][CH:11]=[CH:12][CH:13]=1)[OH:9])=[O:4]
Reactant: O=C(O)Oc1ccccc1O
Reactant: CCN(CC)CC
Agent: CN
Agent: Cl
Solvent: ClCCl
Product: CNC(=O)Oc1ccccc1O

Procedure:
155 g of gaseous methylamine were fed into a solution of 680 g of pyrocatechol carbonate and 555 g of triethylamine in 2.5 liters of methylene chloride at 5° C., with vigorous stirring. 500 g of 36% strength hydrochloric acid were then added and the product was filtered off with suction and washed with water. 801 g (96% of the expected amount) of pyrocatechol methylcarbamate of melting point 125° C. were obtained.
Reaction SMILES: CN([CH:9]=[O:10])C1C=CC=CC=1.P(Cl)(Cl)(Cl)=O.[Cl:16][C:17]1[CH:30]=[CH:29][C:28]2[C:19](=[CH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:18]=1>ClC1C=CC=CC=1Cl>[Cl:16][C:17]1[CH:30]=[CH:29][C:28]2[C:19](=[C:20]([CH:9]=[O:10])[C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:18]=1
Reactant: Clc1ccc2cc3ccccc3cc2c1
Reactant: CN(C=O)c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: Clc1ccccc1Cl
Product: O=Cc1c2ccccc2cc2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.8 %

Procedure:
N-methylformanilide (2.45 kg, 18.12 mol) was treated with phosphorus oxychloride (2.66 kg, 17.35 mol) over a 40 min period at ambient temperature. The intermediate Vilsmeier complex was stirred for 2 h at room temperature, then treated with 2-chloroanthracene (described in example 1a) (963 g, 4.53 mol), and o-dichlorobenzene (1.0 L). The resulting bright yellow mixture was heated gradually over 1.5 h to 9° C. at which point an exotherm ensued raising the reaction temperature to 115° C. The heat was removed until the exotherm subsided (45 min), after which time the mixture was heated for 9 h at 90° C., then cooled. TLC analysis (silica gel; ethyl acetate:hexane 1:4) showed a small amount of unreacted anthracene (Rf 0.90), a small amount of the 3-chloro isomer (Rf 0.65), and the 2-chloro isomer (Rf 0.58) as the major component. The cooled reaction mixture was poured into ice/water (27 L) precipitating a dark brown tar. The aqueous layer was decanted away from the tar and extracted with methylene chloride (5×2 L). The combined extracts were used to redissolve the tar. The methylene chloride solution was washed with 3N hydrochloric acid (4×1.5 L), followed by water (2 L), then dried over magnesium sulfate. The extracts were filtered, then pressure-filtered through a bed of silica gel, eluting with methylene chloride until all of the desired compound had been recovered. The eluent was concentrated on the rotary evaporator to give a slurry of bright yellow crystals (in o-dichlorobenzene). The crystals were collected by filtration, washed with diethyl ether (2×500 ml), then vacuum dried to afford 619.7 g (56.9%) of the desired 2-chloro-9-formylanthracene (mp 148°-150° C.). 1H NMR (CDCl3) 11.35 (s, 1H), 9.02 (d, J=0.9 Hz, 1H), 8.81 (d, J=8.9 Hz, 1H), 8.56 (s, 1H), 7.98 (m, 1H), 7.90 (d, J=8.9 Hz, 1H), 7.66 (m, 1H), 7.53 (m, 1H), 7.42 (m, 1H).
Reaction SMILES: C[O:2][C:3](=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[O:9][C:10]([CH3:20])=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:12]=1.C1COCC1.[OH-].[Na+]>CCO>[OH:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:11]1[N:12]=[C:8]([CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:21])=[O:2])[O:9][C:10]=1[CH3:20]
Reactant: COC(=O)CCCCc1nc(-c2ccccc2O)c(C)o1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1oc(CCCCC(=O)O)nc1-c1ccccc1O

Procedure:
Combine 5-[4-(2-hydroxy-phenyl)-5-methyl-oxazol-2-yl]-pentanoic acid methyl ester (2.9 g, 10.0 mmol) with THF (3 mL), EtOH (3 mL) and 2N NaOH (20 mL) and stir until hydrolysis is complete. Concentrate the mixture, dilute the residue with water and adjust the pH to 2.0-3.0 with aq HCl. Extract the mixture with EtOAc and dry the extracts over Na2SO4 before concentrating. Chromatograph the residue over silica gel (MeOH/CH2Cl2) to allow for recovery of 5-[4-(2-hydroxy-phenyl)-5-methyl-oxazol-2-yl]-pentanoic acid (2.14 g, 78%). MS (ES): (M+1)+ 276.2 m/z.