Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=O)C1C(=CC=CC=1)O.C1C=CC=CC=1.[C:17]([OH:28])(=[O:27])[C:18]1[C:19](=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:20]([OH:22])=O>NC1C=CC=CC=1.[Cu]>[C:20]1(=[O:22])[O:28][C:17](=[O:27])[C:18]2=[CH:26][CH:25]=[CH:24][CH:23]=[C:19]12
Reactant: O=C(O)c1ccccc1C(=O)O
Agent: [Cu]
Agent: O=C(O)c1ccccc1O
Solvent: Nc1ccccc1
Solvent: c1ccccc1
Product: O=C1OC(=O)c2ccccc21

Procedure:
Decarboxylation is not always a predictable reaction. For example, A. S. Sultanov, J. Gen. Chem. (USSR) 16 1835 (1946) as abstracted in CA 41: 6223(e) discloses that salicylic acid may be decarboxylated by autoclaving the acid in the presence of copper bronze and benzene at 170° C. The acid alone decarboxylates at 205° C., while in the presence of aniline decarboxylation begins at 170° C. In the case of salicylic acid, aniline and copper bronze seem to be equal in catalytic ability. On the other hand, when phthalic acid is heated in aniline at 180° C., decarboxylation does not occur and instead phthalic anhydride is produced. Heating phthalic anhydride with copper bronze in chloroform at 180° C. gave a 22% yield of benzoic acid. Phthalic acid was found to decarboxylate to yield benzoic acid merely by heating in water at 235° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([NH:13][CH:14]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)[C:15]([F:18])([F:17])[F:16])=[O:12])=[CH:5][CH:4]=1)#[N:2].[H-].[Na+].[CH3:31]I>CN(C)C=O.C(OCC)(=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([N:13]([CH3:31])[CH:14]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:26])([F:27])[F:28])[CH:20]=2)[C:15]([F:16])([F:17])[F:18])=[O:12])=[CH:5][CH:4]=1)#[N:2]
Reactant: CI
Reactant: N#Cc1ccc(/C=C/C(=O)NC(c2cccc(C(F)(F)F)c2)C(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(C(=O)/C=C/c1ccc(C#N)cc1)C(c1cccc(C(F)(F)F)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
120.0 mg (0.30 mmol) of (2E)-3-(4-cyanophenyl)-N-{2,2,2-trifluoro-1-[3-(trifluoromethyl)-phenyl]ethyl}acrylamide from Synthesis Example 1, Stage 1 were initially charged in 2 ml of N,N-dimethylformamide and admixed at 0° C. with 19.7 mg (0.45 mmol) of sodium hydride (55% oil dispersion). After addition of 64.1 mg (0.45 mmol) of methyl iodide, the mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate, washed three times with water and dried over sodium sulphate. The solvent was distilled off under reduced pressure and the residue purified by preparative HPLC (solvent=water (A)+acetonitrile (B), gradient=40 min, from 10% B to 100% B, flow=18 nm/min).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.C([Li])CCC.[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([C:27](N(OC)C)=[O:28])[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].[OH-].[Na+]>ClCCl.CCCCCC>[Br:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:27]([CH:24]2[CH2:25][CH2:26][N:21]([C:19]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:20])[CH2:22][CH2:23]2)=[O:28])[N:3]=1
Reactant: Brc1cccc(Br)n1
Reactant: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C(=O)c2cccc(Br)n2)CC1
Temperature: -78 °C
Yield: 100.2 %

Procedure:
Dissolve 2,6-dibromopyridine (3.6 g, 15.3 mmol) in anhydrous dichloromethane (90 mL) under nitrogen atmosphere. Cool the reaction mixture to −78° C. Add a solution of n-butyl lithium in hexane very slowly via a syringe (1.6 M, 10.5 mL, 16.9 mmol). After the addition is complete, stir the reaction at −78° C. for 1 hr. Add a solution of 4-(methoxy-methyl-aminocarbonyl)-piperidine-1-carboxylic acid tert-butyl ester (2 g, 7.3 mmol) in anhydrous dichloromethane (10 mL) dropwise to the reaction mixture. Stir the reaction at −78° C. for 2 hrs., then allow it to slowly warm to room temperature overnight. Quench the reaction with 0.1 N aqueous NaOH. Dilute the solution with dichloromethane (100 mL), transfer into a separation funnel and shake with 0.1 N NaOH (60 mL). Separate the organic layer and dry it over anhydrous sodium sulfate. Evaporate the solvent under reduced pressure. Further purify the residue by chromatography on silica gel column (10%-30% ethyl acetate/hexane) to obtain 2-bromo-6-(1-t-butoxycarbonylpiperidin-4-ylcarbonyl)-pyridine (2.7 g, quantitative yield). Mass spectrum (ion spray): m/z 370 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5]([NH:6][CH:7]=[N:8][C:9]=2[Cl:11])=[N:4][CH:3]=1.[O:12]1[CH2:15][CH:14](O)[CH2:13]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCOCC1>[Br:1][C:2]1[C:10]2[C:9]([Cl:11])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH:14]2[CH2:15][O:12][CH2:13]2)[CH:3]=1
Reactant: Clc1nc[nH]c2ncc(Br)c1-2
Reactant: OC1COC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: Clc1ncnc2c1c(Br)cn2C1COC1
Temperature: 85 °C
Yield: 42.1 %

Procedure:
To 5-bromo-4-chloro-1H-pyrrolo[2,3-d]pyrimidine (300 mg, 1.291 mmol) were added 3-oxetanol (287 mg, 3.87 mmol), polymer bound triphenylphosphine (860 mg, 2.58 mmol) resin and 1,4-Dioxane (2 mL) into a 5 mL microwave vial then DEAD (0.409 mL, 2.58 mmol) was added. The reaction vial was then capped and heated in microwave reactor for 15 minutes at 85° C. The reaction was not complete so it was heated for a total of 1 hr and the reaction was filtered, concentrated, diluted with EtOAc (10 mL) then washed water (10 ml). The water was back extracted with EtOAc (2×10 ml). The organics were combined then washed with brine, dried over MgSO4, filtered and concentrated. The crude was loaded on to a 10 g Biotage column and purified with 0 to 40% EtOAc in Hexane gradient over 30 minutes to afford 5-bromo-4-chloro-7-(3-oxetanyl)-7H-pyrrolo[2,3-d]pyrimidine (157 mg 42.2% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.45 (s, 1H), 5.95 (t, J=7.07 Hz, 1H), 4.96-5.04 (m, J=7.07, 7.33, 7.45, 7.45 Hz, 4H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:9]=1)[CH:7]=[O:8].[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)#[CH:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:12]1([C:10]#[C:11][C:2]2[CH:3]=[N:4][CH:5]=[C:6]([CH:9]=2)[CH:7]=[O:8])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1cncc(Br)c1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: O=Cc1cncc(C#Cc2ccccc2)c1
Temperature: 25 °C

Procedure:
A solution of 5-bromonicotinaldehyde (15 g, 81 mmol) and ethynylbenzene (9.74 mL, 89 mmol) in triethylamine (150 mL) was purged with nitrogen for 30 min. The reaction was treated with triphenylphosphine (0.656 g, 2.50 mmol), and purged 10 minutes longer. To this was added bis(triphenylphosphine)palladium dichloride (0.147 g, 0.210 mmol) and copper(I) iodide (0.032 g, 0.169 mmol). After purging 10 min longer, the reaction was warmed to a gentle reflux. The reaction was heated at reflux for 24 h. The reaction was cooled to room temperature, diluted with ethyl acetate, poured into water, and the layers were separated. The organics were washed again with water, then brine, dried over magnesium sulfate, and concentrated. Column chromatography (20% EtOAc/Hex) gave 16.05 g (96%) as faint yellow crystalline solid. 1H NMR (CDCl3) δ: 10.16 (s, 1H), 9.01 (dd, J=17.1, 1.8 Hz, 2H), 8.30 (t, J=2.0 Hz, 1H), 7.54-7.66 (m, 2H), 7.38-7.47 (m, 3H). 13C NMR (CDCl3) δ: 190.2, 156.8, 150.3, 138.2, 131.9, 130.9, 129.4, 128.7, 122.0, 121.5, 94.5, 84.7. Mass spec.: 208.0 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[NH:3][N:4]=[CH:5][CH:6]=1.FC1C=CC(C(O[C:15]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[CH:16][C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=O)=CC=1>CCO.Cl.C(Cl)(Cl)Cl.CO>[F:29][C:26]1[CH:25]=[CH:24][C:23]([C:15]2[C:16]([C:17]3[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=3)=[C:15]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[N:1]=[C:2]3[NH:3][N:4]=[CH:5][C:6]=23)=[CH:28][CH:27]=1
Reactant: Nc1ccn[nH]1
Reactant: O=C(OC(=Cc1ccncc1)c1ccc(F)cc1)c1ccc(F)cc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCO
Solvent: CO
Product: Fc1ccc(-c2nc3[nH]ncc3c(-c3ccc(F)cc3)c2-c2ccncc2)cc1
Yield: 0.5 %

Procedure:
To a solution of 3-amino-2H-pyrazole (60 mg, 71.8 mmol) in EtOH (2 mL) and 1 drop of 37% HCl, 1-(4-fluorophenyl)-2-(4-pyridyl)vinyl 4-fluorobenzoate (0.22 g, 65.0 mmol, obtained in reference example 4) was added under argon atmosphere. This was heated to reflux for 3 days. The mixture was diluted with CHCl3 and MeOH. It was washed with saturated NaHCO3. The aqueous phase was extracted with CHCl3 (×2). The organic phase was dried over Na2SO4 and concentrated to dryness. The crude product obtained was purified by chromatography on silica gel using hexane-EtOAc mixtures of increasing polarity as eluent, to afford 58 mg of the desired product in a solid white form (yield: 23%).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.[CH:7](=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH2:7]([N:4]1[CH2:5][CH2:6][C@H:2]([OH:1])[CH2:3]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O[C@H]1CCNC1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: O[C@H]1CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.2 %

Procedure:
A solution of (3S)-3-hydroxypyrrolidine (2.0 g, 25 mmol) in 50 mL CH2Cl2, under a nitrogen atmosphere, was cooled to 0° C. and benzaldehyde (2.92 g. 27.5 mmol) was added, followed by 1 g of powdered 4A molecular sieves. Sodium triacetoxyborohydride (7.4 gm, 35 mmol)was added in several portions over 30 min, and the reaction was allowed to stir at room temperature for 18 h. The reaction was again cooled to 0° C. and quenched by addition of 10 mL methanol, followed by 5 mL of 1N HCl. The molecular sieve solids were removed by filtration through a glass fiber paper, and the filtrate was extracted with 20 mL diethyl ether. The organic phase was discarded, and the aqueous phase was first basified by addition of conc. ammonium hydroxide, and then extracted with EtOAc (3×20 mL). The combined extracts were washed with 20 mL brine, dried (MgSO4), filtered, and concentrated in vacuo to furnish 3.2 g (73%) of clear yellow oil, which required no further purification. 1H-NMR (400 MHz, CDCl3) δ 7.2-7.4 (m, 5H), 4.33 (m, 1H), 3.63, (s, 2H), 2.83-3.89 (m, 1H), 2.67 (d, J=9.9 Hz, 1H), 2.53-2.55 (m, 1H), 2.23-2.34 (m, 1H), 2.14-2.20 (m, 2H), 1.70-1.77 (m, 1H).
Reaction SMILES: [NH:1]([C:8](=[O:28])[CH:9]([C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][CH:20]=1)[C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:29][C:30]1[C:34]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])(C)C)=[CH:33][N:32]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[N:31]=1.[CH:49](N(CC)C(C)C)(C)[CH3:50].F[P-](F)(F)(F)(F)F.N1(O[P+](C(C)C)(C(C)C)C(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[NH:12]([C:10](=[O:11])[CH:9]([C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH:29][C:30]2[C:34]([NH:35][C:36](=[O:42])[O:37][CH2:38][CH2:41][CH2:49][CH3:50])=[CH:33][N:32]([C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)[N:31]=2)=[O:25])=[CH:21][CH:20]=1)[C:8]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:28])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)Nc1cn(-c2ccccc2)nc1N
Reactant: O=C(O)c1ccc(C(C(=O)Nc2ccccc2)C(=O)Nc2ccccc2)cc1
Reactant: CCN(C(C)C)C(C)C
Agent: CC(C)[P+](On1nnc2ccccc21)(C(C)C)C(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CCCCOC(=O)Nc1cn(-c2ccccc2)nc1NC(=O)c1ccc(C(C(=O)Nc2ccccc2)C(=O)Nc2ccccc2)cc1
Temperature: 60 °C

Procedure:
To a solution of 4-[2-anilino-1-(anilinocarbonyl)-2-oxoethyl]benzoic acid (0.3 g, 0.8 mmol), tert-butyl (3-amino-1-phenyl-1H-pyrazol-4-yl)carbamate (0.28 g, 1.0 mmol) and N,N-diisopropylethylamine (0.11 g, 0.88 mmol) in methylene chloride (5 mL) was added (1H-1,2,3-benzotriazol-1-yloxy)(triisopropyl)phosphonium hexafluorophosphate (0.53 g, 1.2 mmol). The reaction vessel was sealed and heated to 60° C. for 16 hours. The product was purified by flash chromatography (0-3% methanol/methylene chloride) to give crude ten-butyl [3-({4-[2-anilino-1-(anilinocarbonyl)-2-oxoethyl]benzoyl}amino)-1-phenyl-1H-pyrazol-4-yl]carbamate as a white solid. ESIMS calcd 631.3 (M++H), found 631.2 (M++H).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@H:18]([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].[F:26][C:27]([F:44])([F:43])[C@H:28]([O:30][C:31](=O)[O:32]C1C=CC([N+]([O-])=O)=CC=1)[CH3:29]>>[F:26][C:27]([F:44])([F:43])[C@H:28]([O:30][C:31]([N:23]1[CH2:24][CH2:25][CH:20]([C@@H:18]2[O:17][C:14]3=[CH:15][N:16]=[C:11]([C:8]4[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH2:6][CH:7]=4)[CH:12]=[C:13]3[CH2:19]2)[CH2:21][CH2:22]1)=[O:32])[CH3:29]
Reactant: CS(=O)(=O)N1CC=C(c2cc3c(cn2)O[C@@H](C2CCNCC2)C3)CC1
Reactant: C[C@@H](OC(=O)Oc1ccc([N+](=O)[O-])cc1)C(F)(F)F
Product: C[C@@H](OC(=O)N1CCC([C@H]2Cc3cc(C4=CCN(S(C)(=O)=O)CC4)ncc3O2)CC1)C(F)(F)F

Procedure:
The title compound is prepared from (R)-5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine and carbonic acid 4-nitro-phenyl ester (R)-2,2,2-trifluoro-1-methyl-ethyl ester following a procedure analogous to that described for Example 1. LC (method 2): tR=0.97 min; Mass spectrum (ESI+): m/z=504 [M+H]+.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([Cl:9])=[CH:7][C:6]([NH:10][C:11]2[C:12]3[C:19]4[CH2:20][CH2:21][NH:22][CH2:23][C:18]=4[S:17][C:13]=3[N:14]=[CH:15][N:16]=2)=[CH:5][C:4]=1[OH:24].Cl.[CH3:26][N:27]([CH:34]([CH3:36])[CH3:35])[CH2:28]/[CH:29]=[CH:30]/[C:31](O)=[O:32].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[Cl:2][C:3]1[C:8]([Cl:9])=[CH:7][C:6]([NH:10][C:11]2[C:12]3[C:19]4[CH2:20][CH2:21][N:22]([C:31](=[O:32])/[CH:30]=[CH:29]/[CH2:28][N:27]([CH3:26])[CH:34]([CH3:36])[CH3:35])[CH2:23][C:18]=4[S:17][C:13]=3[N:14]=[CH:15][N:16]=2)=[CH:5][C:4]=1[OH:24]
Reactant: CC(C)N(C)C/C=C/C(=O)O
Reactant: Oc1cc(Nc2ncnc3sc4c(c23)CCNC4)cc(Cl)c1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)N(C)C/C=C/C(=O)N1CCc2c(sc3ncnc(Nc4cc(O)c(Cl)c(Cl)c4)c23)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.1 %

Procedure:
2,3-Dichloro-5-(5,6,7,8-tetrahydropyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-ylamino)phenol hydrochloride from Example 69A (51 mg, 0.13 mmol) and (2E)-4-[methyl(1-methylethyl)amino]but-2-enoic acid hydrochloride from Example 2A (34 mg, 0.18 mmol) were dissolved in DMF (1.5 mL), and DIPEA (82 mg, 0.63 mmol) and TBTU (61 mg, 0.19 mmol) were added. The mixture was stirred at rt overnight. The product was then directly isolated by preparative HPLC to yield 33 mg (52%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:6][CH:5]=[C:4]([Cl:16])[C:3]=1[NH:17][C:18]1[N:39]([CH3:40])[C:21]2=[N:22][C:23]([N:29]3[CH2:34][CH2:33][CH:32]([C:35]([F:38])([F:37])[F:36])[CH2:31][CH2:30]3)=[C:24]([C:26](O)=[O:27])[CH:25]=[C:20]2[N:19]=1.ClC(N(C)C)=C(C)C.[F:49][C:50]([F:60])([F:59])[O:51][C:52]1[CH:58]=[CH:57][C:55]([NH2:56])=[CH:54][CH:53]=1.N1C=CC=CC=1>CC#N.C(Cl)Cl>[F:49][C:50]([F:59])([F:60])[O:51][C:52]1[CH:53]=[CH:54][C:55]([NH:56][C:26]([C:24]2[CH:25]=[C:20]3[N:19]=[C:18]([NH:17][C:3]4[C:4]([Cl:16])=[CH:5][CH:6]=[C:7]([CH2:8][NH:9][C:10](=[O:15])[C:11]([CH3:13])([CH3:14])[CH3:12])[C:2]=4[Cl:1])[N:39]([CH3:40])[C:21]3=[N:22][C:23]=2[N:29]2[CH2:30][CH2:31][CH:32]([C:35]([F:36])([F:38])[F:37])[CH2:33][CH2:34]2)=[O:27])=[CH:57][CH:58]=1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: Cn1c(Nc2c(Cl)ccc(CNC(=O)C(C)(C)C)c2Cl)nc2cc(C(=O)O)c(N3CCC(C(F)(F)F)CC3)nc21
Agent: CC(C)=C(Cl)N(C)C
Solvent: CC#N
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cn1c(Nc2c(Cl)ccc(CNC(=O)C(C)(C)C)c2Cl)nc2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)c(N3CCC(C(F)(F)F)CC3)nc21
Reaction time: 0.5 h

Procedure:
A mixture of 2-{2,6-dichloro-3-[(2,2-dimethyl-propionylamino)-methyl]-phenylamino}-5-[4-trifluoromethyl-piperidinyl]-3-methyl-3H-imidazo[4,5-b]pyridine-6-carboxylic acid (54 mg, 0.090 mmol), (1-chloro-2-methyl-propenyl)-dimethylamine (0.026 mL, 0.20 mmol) and DCM (2 mL) is stirred for 30 min. This mixture is added to 4-trifluoromethoxyaniline (0.100 mmol) and pyridine (25 μL, 0.32 mmol) in MeCN (1 mL) and it is stirred for 2 h at 40° C. and overnight at 60° C. The mixture is concentrated and the residue is diluted with DMF/water 19/1 (2 mL) and purified via reverse phase HPLC. Yield: 18 mg. HPLC Rt=0.645 min (method G). MS m/z: 760 [M+H]+.
Reaction SMILES: O[CH:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([O:12]COC)[C:6]=2[CH2:5][CH:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:3]1.C[Si]([C:26]#[N:27])(C)C.B(F)(F)F.CCOCC.O>C(Cl)Cl>[C:26]([CH:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([OH:12])[C:6]=2[CH2:5][CH:4]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[O:3]1)#[N:27]
Reactant: C[Si](C)(C)C#N
Reactant: COCOc1cccc2c1CC(c1ccccc1)OC2O
Agent: FB(F)F
Solvent: CCOCC
Solvent: O
Solvent: ClCCl
Product: N#CC1OC(c2ccccc2)Cc2c(O)cccc21
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 92 %

Procedure:
A solution of 9.07 g (31.7 mmol) of 3,4-dihydro -1-hydroxy-5-methoxymethoxy-3-phenyl-1H-2-benzopyran, from Step 2 above, in 150 mL of methylene chloride at -78° C. was treated, sequentially, with trimethylsilyl cyanide (8.5 mL, 64 mmol) and boron trifluoride etherate (6 mL, 49 mmol). After being stirred for 1.5 h at -78° C., and for 4 h at ambient temperature, 100 mL of water was added and stirring was continued for 1 h. The reaction mixture was then extracted with 2×300 mL of ethyl acetate and the combined organic extract was washed with 200 mL of brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified on silica gel eluted with 10% ethyl acetate in hexane to give 7.33 g (92% yield) of the title compound as a 4:1 mixture of the trans and cis isomers.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9]C(=O)C.Cl>C(O)C>[Cl-:1].[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH3+:9]
Reactant: CC(=O)Nc1ccc(F)cc1Cl
Agent: Cl
Solvent: CCO
Product: [Cl-]
Product: [NH3+]c1ccc(F)cc1Cl
Temperature: 0 °C
Yield: 165.2 %

Procedure:
A mixture of N-(2-chloro-4-fluorophenyl)acetamide (25.0 g, 133 mmol), concentrated hydrochloric acid (25 ml) and ethanol(50 ml) was heated at reflux for 3 h. The mixture was cooled to 0° C. and left for crystallisation. The precipitate was collected and dried in vacuo to give 20.0 g of 2-chloro-4-fluorophenylammonium chloride.
Reaction SMILES: [Mg].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[F:13][C:14]1[C:22]([CH3:23])=[C:21]([F:24])[C:20]([F:25])=[CH:19][C:15]=1[C:16](Cl)=[O:17].S(=O)(=O)(O)O>C1(C)C=CC=CC=1.C(O)C.C(Cl)(Cl)(Cl)Cl>[F:13][C:14]1[C:22]([CH3:23])=[C:21]([F:24])[C:20]([F:25])=[CH:19][C:15]=1[C:16]([CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:2]([O:10][CH2:11][CH3:12])=[O:9])=[O:17]
Reactant: Cc1c(F)c(F)cc(C(=O)Cl)c1F
Reactant: CCOC(=O)CC(=O)OCC
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: ClC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)C(C(=O)OCC)C(=O)c1cc(F)c(F)c(C)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 112.7 %

Procedure:
To a mixture of magnesium turnings (0.69 g) and absolute ethanol (4.7 ml) was added carbon tetrachloride (0.4 ml). To the stirring suspension was added a solution of diethyl malonate (4.41 g) and absolute ethanol (4.7 ml) in anhydrous toluene (19.2 ml) dropwise during 10 minutes at 15° to 50° C. After the mixture was stirred at 50° to 60° C. for 2 hours, to the mixture was added a solution of 2,4,5-trifluoro-3-methylbenzoyl chloride (4.51 g) in anhydrous toluene (6.4 ml) dropwise at -16° to -13° C. during 10 minutes. The reacting mixture was stirred at -20° C. for 1 hour, and then warmed gradually to room temperature during 1.5 hours with stirring. To this solution was added ice water (25 ml) containing concentrated sulfuric acid (0.8 ml), extracted with toluene. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium chloride and concentrated under reduced pressure to give the title compound (8.10 g).
Reaction SMILES: Cl[C:2]1[C:11]2[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7][C:6]=2[C:5](B(O)O)=[CH:4][N:3]=1.Br[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[N:18]=1.[NH2:24][C:25]1[N:26]=[C:27]([CH3:30])[S:28][CH:29]=1>>[CH3:12][C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[C:2]([NH:24][C:25]3[N:26]=[C:27]([CH3:30])[S:28][CH:29]=3)[N:3]=[CH:4][C:5]=2[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[N:18]=2)[N:10]=1
Reactant: Cc1cccc(Br)n1
Reactant: Cc1nc(N)cs1
Reactant: Cc1ccc2c(B(O)O)cnc(Cl)c2n1
Product: Cc1cccc(-c2cnc(Nc3csc(C)n3)c3nc(C)ccc23)n1

Procedure:
The title compound, MS: m/e=348.2 (M+H+), was prepared in accordance with the general method of example 15 step 1 and step 3 from 8-chloro-2-methyl-[1,7]naphthyridine-5-boronic acid (Example L), 2-bromo-6-methylpyridine and 4-amino-2-methylthiazole (Example F).
Reaction SMILES: C([O:8][CH2:9][C@@H:10]1[C@@H:13]([CH2:14][O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12][C:11]1=[O:23])C1C=CC=CC=1.[Cl-].[Cl-].[CH2:26]([Al+2])C(C)C>C1(C)C=CC=CC=1>[OH:23][CH:11]1[CH2:12][CH:13]([CH2:14][OH:15])[CH:10]1[CH2:9][OH:8].[CH2:16]([O:15][CH2:14][C:13]1[CH:10]=[CH:9][CH:26]=[CH:11][CH:12]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C1C[C@H](COCc2ccccc2)[C@H]1COCc1ccccc1
Reactant: CC(C)C[Al+2]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: OCC1CC(O)C1CO
Product: c1ccc(COCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of (2S-trans) -2,3-bis [(benzyloxy)-methyl]cyclobutanone (0.5 g., 1.61 mmole) in toluene (1 ml. ) was added dropwise to a solution of isobutylaluminum dichloride (0.71 M in hexane, 3.41 ml., 2.42 mmole) at -78° C. The mixture was allowed to warm slowly to room temperature over 2 hours. After stirring for 30 minutes at room temperature, the mixture was allowed to stand at 0° C. overnight. After dilution with ethyl acetate, the reaction mixture was quenched with 10% hydrochloric acid. The organic phase was washed with brine, dried (magnesium sulfate) and the solvent evaporated to give [1S-(1α, 2β, 3β)]-3-hydroxy-1,2-cyclobutanedimethanol, dibenzyl ether; TLC (50% ethyl acetate/hexane ) Rf =0.53.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:12](OC1C=CC([N+]([O-])=O)=CC=1)=[O:13].C(N(CC)CC)C.[Cl:31][C:32]1[CH:41]=[C:40]2[C:35]([C:36]([N:42]3[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]3)=[CH:37][CH:38]=[N:39]2)=[CH:34][CH:33]=1>>[Cl:31][C:32]1[CH:41]=[C:40]2[C:35]([C:36]([N:42]3[CH2:47][CH2:46][N:45]([C:12]([NH:10][CH2:9][CH2:8][CH2:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[O:13])[CH2:44][CH2:43]3)=[CH:37][CH:38]=[N:39]2)=[CH:34][CH:33]=1
Reactant: Clc1ccc2c(N3CCNCC3)ccnc2c1
Reactant: NCCCc1ccccc1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Product: O=C(NCCCc1ccccc1)N1CCN(c2ccnc3cc(Cl)ccc23)CC1

Procedure:
3-Phenyl-1-propylamine (71 μL, 0.5 mmol), 4-nitrophenyl chloroformate (101 mg, 0.5 mmol), triethylamine (154 μL, 1.1 mmol), and 7-chloro-4-(piperazin-1-yl)quinoline (124 mg, 0.5 mmol) are treated according to method D delivering the title product as a colorless oil after column chromatography with hexane-EtOAc.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[F:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[F:20])[CH2:15]Br>>[F:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[F:20])[CH2:15][N:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]([CH2:15][C:14]2[CH:17]=[CH:18][C:19]([F:20])=[C:12]([F:11])[CH:13]=2)[C:2]1=[NH:1]
Reactant: Fc1ccc(CBr)cc1F
Reactant: Nc1nc2ccccc2[nH]1
Product: N=c1n(Cc2ccc(F)c(F)c2)c2ccccc2n1Cc1ccc(F)c(F)c1

Procedure:
The title compound was prepared from 2-aminobenzimidazole and 3,4-difluorobenzyl bromide by Procedure A. The product was isolated by preparative LCMS to give the title compound as the free base (white solid, mp 114-117° C.). MS(ES+) m/z 387 ([M+1]+, 100). 1NMR (DMSO-d6) δ 5.08 (br s, 4H), 5.86 (br s, 1H), 6.72-6.96 (m, 4H), 7.05-7.22 (m, 2H), 7.35-7.45 (m, 4H).