Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9](=[O:24])[C@H:10]([CH3:23])[C@H:11]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:12](O)=O)C1C=CC=CC=1.CN1CCOCC1.ClC(OCC(C)C)=O.[C:40]([C:44]1[CH:45]=[C:46]([NH2:51])[C:47]([NH2:50])=[CH:48][CH:49]=1)([CH3:43])([CH3:42])[CH3:41]>O1CCCC1>[C:19]([O:18][C:16]([NH:15][C@H:11]([C:12]1[NH:50][C:47]2[CH:48]=[CH:49][C:44]([C:40]([CH3:43])([CH3:41])[CH3:42])=[CH:45][C:46]=2[N:51]=1)[C@@H:10]([CH3:23])[C:9]([OH:24])=[O:8])=[O:17])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)c1ccc(N)c(N)c1
Reactant: C[C@@H](C(=O)OCc1ccccc1)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: C[C@@H](C(=O)O)[C@H](NC(=O)OC(C)(C)C)c1nc2cc(C(C)(C)C)ccc2[nH]1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 77.3 %

Procedure:
To a cooled solution (−78° C.) of (2S,3R)-4-(benzyloxy)-2-((tert-butoxycarbonyl)amino)-3-methyl-4-oxobutanoic acid (Preparation 66, 4.10 g, 12.2 mmol) in tetrahydrofuran (50 mL) was added N-methylmorpholine (2.0 mL, 18.23 mmol) followed by isobutyl chloroformate (1.67 mL, 12.8 mmol) and the resulting white suspension stirred at −78° C. for 30 minutes. A solution of 4-(tert-butyl)benzene-1,2-diamine (2.40 g, 14.6 mmol) in tetrahydrofuran (5 mL) was added. The reaction mixture was allowed to warm up to room temperature and stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo. The crude product was dissolved in ethyl acetate (200 mL) and washed with aqueous saturated sodium bicarbonate (3×50 mL), water (2×50 mL). The organic layer was concentrated in vacuo and purified by silica gel column chromatography eluting with a gradient of dichloromethane: EtOAc. The residue was dissolved in methanol (50 mL) and palladium hydroxide was added (20% wt % on carbon, 0.43 g). The reaction mixture was stirred under a hydrogen atmosphere (2 atm) at room temperature for 1 hour. The reaction mixture was filtered through a small pad of Arbocel and concentrated in vacuo. The residue was dissolved in acetic acid (100 mL) and stirred at room temperature for 72 hours. The reaction mixture was concentrated in vacuo. The crude product was purified by reverse phase column chromatography eluting with a gradient of water/MeCN to afford the title compound as off-white solid (3.54 g, 78%).
Reaction SMILES: C([Cl:4])(=O)C.[N:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:15][CH2:14][C:13]3([CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]3)[CH2:12]2)=[CH:7][CH:6]=1>C(O)C>[ClH:4].[ClH:4].[N:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:15][CH2:14][C:13]3([CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[CH2:12]2)=[CH:9][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CCN(c1ccncc1)C2
Reactant: CC(=O)Cl
Solvent: CCO
Product: Cl
Product: c1cc(N2CCC3(CCNCC3)C2)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
Acetyl chloride (5 eq.) was added to an ice-cold solution of tert-butyl 2-(pyridin-4-yl)-2,8-diazaspiro[4.5]decane-8-carboxylate (3.78 mmol, 1 eq.) in ethanol (14 ml). The reaction mixture was stirred at room temperature overnight. The solvent was concentrated in vacuo and the residue was dissolved in ethanol/acetone (2:1, 30 ml). The white solid which precipitated was filtered out, washed with diethyl ether and dried in vacuo. Yield: 98%
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[N:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]#[C:14][C:15]1[O:19][C:18]([CH:20]=O)=[CH:17][CH:16]=1.[C:22]([N+:26]#[C-:27])([CH3:25])([CH3:24])[CH3:23].Cl(O)(=O)(=O)=O.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl.C(Cl)Cl>[C:22]([NH:26][C:27]1[N:6]2[C:2]([S:3][CH:4]=[CH:5]2)=[N:1][C:20]=1[C:18]1[O:19][C:15]([C:14]#[C:13][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][N:7]=2)=[CH:16][CH:17]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: O=Cc1ccc(C#Cc2ccccn2)o1
Reactant: [C-]#[N+]C(C)(C)C
Reactant: Nc1nccs1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC(C)(C)Nc1c(-c2ccc(C#Cc3ccccn3)o2)nc2sccn12
Reaction time: 16 h
Yield: 34.2 %

Procedure:
A solution of 380 mg (3.8 mmol) 2-amino-thiazole, 749 mg (3.8 mmol) 5-(pyridine-2-yl-ethynyl)-furan-2-carbaldehyde, 378 mg (3.8 mmol) tert.butyl-isonitril and 73 μl of a 70% aq. perchloric acid in chloroform (2 ml) was heated to 45° C. while being stirred for 16 h. Dilution with DCM was subsequently performed and a 1 molar aq. Na2CO3 sol. was added. After 10 min of stirring at RT, the phases were separated. The aqueous phase was extracted with DCM. The collected organic phases were dried over Na2SO4, filtered and concentrated in a vacuum. 472 mg (1.3 mmol, 34%) N-tert-butyl-6-(5-(pyridine-2-ylethynyl)furan-2-yl)imidazo[2,1-b]thiazole-5-amine was obtained by CC (AE) with the residue.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:24][C:25]([CH3:28])([O-])[CH3:26].[K+].C[C:31]1[CH:32]=CC=[C:35]2[C:39]=1[NH:38][N:37]=[C:36]2C=O>>[CH3:2][O:3][CH:4]=[CH:24][C:25]1[CH:28]=[C:35]2[C:39](=[C:31]([CH3:32])[CH:26]=1)[NH:38][N:37]=[CH:36]2
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1cccc2c(C=O)n[nH]c12
Reactant: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Product: COC=Cc1cc(C)c2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 94.3 %

Procedure:
Methoxymethyl triphenylphosphonium chloride (2.74 g, 8 mmol, 2.0 equiv.) and potassium tert-butoxide (1.35 g, 12 mmol, 3.0 equiv.) were weighed into a 250-mL oven-dried flask. Tetrahydrofuran (15 mL) was slowly introduced via syringe under nitrogen. After the resulting red solution was stirred at room temperature for 10 min, 7-methylindazole aldehyde (641 mg, 1.0 equiv.) was added in one portion. LCMS indicated that the reaction was complete within 1 h. The reaction was quenched with water and the mixture was then diluted with ethyl acetate. The layers were separated and the organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo to give a tan oil. The crude product was purified by flash column chromatography on silica gel (1:1 hexane/ethyl acetate) to afford the desired product as an off-white solid (710 mg, 94%). MS (ESI) [M+H]+=189; 1H NMR indicated a mixture of isomers (trans/cis ˜3:1). Trans isomer: 1H-NMR (400 MHz, CDCl3) δ 12.3 (br., 1H), 8.13 (s, 1H), 7.88 (s, 1H), 7.42 (s, 1H), 6.12 (d, J=7.0 Hz, 1H), 5.31 (d, J=7.0 Hz, 1H), 3.80 (s, 3H), 2.60 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1(C(O)=O)[C:7]2([CH2:9][CH2:8]2)[CH2:6]1)=[O:4].C1C=CC(P([N:27]=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.CCN(CC)CC.[ClH:37].O1CCOCC1>CC(O)(C)C>[ClH:37].[CH3:1][O:2][C:3]([C:5]1([NH2:27])[C:7]2([CH2:9][CH2:8]2)[CH2:6]1)=[O:4]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: COC(=O)C1(C(=O)O)CC12CC2
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)(C)O
Solvent: CCN(CC)CC
Product: COC(=O)C1(N)CC12CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 20 %

Procedure:
To a mixture of spiro[2.2]pentane-1,1-dicarboxylic acid methyl ester (400 mg, 2.30 mmol) in 3 mL of anhydrous t-BuOH was added 700 mg (2.50 mmol) of DPPA and 278 mg (2.70 mmol) of Et3N. The mixture was heated at reflux for 21 h and then partitioned between H2O and ether. The ether phase was dried over magnesium sulfate, filtered and concentrated in vacuo to yield an oil. To this oil was added 3 mL of a 4 M HCl/dioxane solution. This acidic solution was stirred at rt for 2 h and then concentrated in vacuo. The residue was triturated with ether to give 82 mg (20%) of 1-amino-spiro[2.2]pentane-1-carboxylic acid methyl ester hydrochloride salt as a white solid. 1H NMR (300 MHz, CDCl3) δ 9.19 (br s, 3 H), 3.81 (s, 3 H), 2.16, (d, J=5.5 Hz, 1 H), 2.01 (d, J=5.5 Hz, 1 H), 1.49 (m, 1 H), 1.24, (m, 1 H), 1.12 (m, 2 H). LRMS of free amine: MS m/z 142 (M++1). Section 2 of Example 12 The following P1′ intermediates were prepared as described: 1. Preparation of Cyclopropylsulfonamide (Alternate Route):
Reaction SMILES: [F:1][C:2]1([F:28])[CH2:4][CH:3]1[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]3[CH:22]=[C:21]([CH2:23]O)[CH:20]=[CH:19][C:16]=3[C:17]#[N:18])=[CH:14][C:9]=2[N:8]([CH3:25])[S:7]1(=[O:27])=[O:26].C(N(CC)CC)C.S(Cl)(C)(=O)=O.[O:41]1[C:49]2[CH2:48][CH2:47][NH:46][CH2:45][C:44]=2[C:43]([OH:50])=[N:42]1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[F:28][C:2]1([F:1])[CH2:4][CH:3]1[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]3[CH:22]=[C:21]([CH2:23][N:46]4[CH2:47][CH2:48][C:49]5[O:41][N:42]=[C:43]([OH:50])[C:44]=5[CH2:45]4)[CH:20]=[CH:19][C:16]=3[C:17]#[N:18])=[CH:14][C:9]=2[N:8]([CH3:25])[S:7]1(=[O:27])=[O:26]
Reactant: Oc1noc2c1CNCC2
Reactant: CN1c2cc(-c3cc(CO)ccc3C#N)ccc2N(CC2CC2(F)F)S1(=O)=O
Agent: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CN1c2cc(-c3cc(CN4CCc5onc(O)c5C4)ccc3C#N)ccc2N(CC2CC2(F)F)S1(=O)=O
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
2-{1-[(2,2-difluorocyclopropyl)methyl]-3-methyl-2,2-dioxido-1,3-dihydro-2,1,3-benzothiadiazol-5-yl}-4-(hydroxymethyl)benzonitrile (4-3) (30 mg, 0.07 mmol, 1 eq) was dissolved in NMP (1 mL) and triethylamine (0.03 mL, 0.22 mmol, 3 eq) was added followed by mesyl chloride (0.006 mL, 0.08 mmil, 1.1 eq). After 10 minutes, 4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridin-3-ol (23.2 mg, 0.16 mmol, 2 eq) and DIPEA (0.085 mL, 0.49 mmol, 6 eq) were added. The resulting mixture stirred at 80° C. for 1 h. The mixture was cooled and purified by reverse phase chromatography (Waters Sunfire MSC18, 10-100% acetonitrile in water with 0.1% TFA modifier) to afford 2-{1-[(2,2-difluorocyclopropyl)methyl]-3-methyl-2,2-dioxido-1,3-dihydro-2,1,3-benzothiadiazol-5-yl}-4-[(3-hydroxy-6,7-dihydroisoxazolo[4,5-c]pyridin-5(4H)-yl)methyl]benzonitrile (20-1) as a white solid. HRMS m/z (M+H) 528.1521 found, 528.1512 required.
Reaction SMILES: C1C2C(COC([NH:18][C@H:19]([C:43]([NH:45][CH2:46][CH2:47][C:48]3[CH:55]=[CH:54][C:52]([OH:53])=[C:50]([OH:51])[CH:49]=3)=[O:44])[CH2:20][C:21](=[O:42])[NH:22][C:23]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=O)C3C(=CC=CC=3)C=2C=CC=1.[C:56]([OH:68])(=O)/[CH:57]=[CH:58]/[C:59]1[CH:66]=[CH:65][C:63]([OH:64])=[C:61]([OH:62])[CH:60]=1>>[C:56]([NH:18][C@H:19]([C:43]([NH:45][CH2:46][CH2:47][C:48]1[CH:55]=[CH:54][C:52]([OH:53])=[C:50]([OH:51])[CH:49]=1)=[O:44])[CH2:20][C:21](=[O:42])[NH:22][C:23]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:68])/[CH:57]=[CH:58]/[C:59]1[CH:66]=[CH:65][C:63]([OH:64])=[C:61]([OH:62])[CH:60]=1
Reactant: O=C(C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NCCc1ccc(O)c(O)c1)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(O)/C=C/c1ccc(O)c(O)c1
Product: O=C(/C=C/c1ccc(O)c(O)c1)N[C@@H](CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)NCCc1ccc(O)c(O)c1

Procedure:
N-[Nα-(9-fluorenylmethoxycarbonyl)-Nγ-trityl-L-asparagyl]dopamine (1.0 g, 1.5 mmol) was deprotected according to the indications of general procedure G. The intermediate was coupled with caffeic acid (348 mg, 2.2 mmol) following general procedure D. The crude material was purified by flash chromatography using a solvent gradient from 30% to 70% EtOAc/CHCl3 containing 1% AcOH. The final product was obtained as yellow powder (400 mg, 44%).
Reaction SMILES: [CH:1]([C:3]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:4]=1[O:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=O.C1CCN2C(=NCCC2)CC1.CO>CCOC(C)=O>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:3]2[CH:1]=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[O:5][C:4]=2[CH:12]=1
Reactant: CCOC(=O)COc1cc(OC)ccc1C=O
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CO
Product: CCOC(=O)c1cc2ccc(OC)cc2o1
Temperature: 160 °C
Yield: 93.9 %

Procedure:
A mixture of the product of Step A (1.28 g, 5.37 mmol) and DBU (0.3 ml) was heated for 3 h at 160° C. with stirring, cooled to room temperature and dissolved in EtOAc:MeOH mixture (99:1). The mixture was filtered through the silica bead and the filtrate was evaporated to give the title compound (1.11 g; 77%), as colourless solid. 1H-NMR (CDCl3) 1.40 (tr, 3H, J=7.13 Hz); 3.85 (s, 3H); 4.40 (q, 2H, J=7.13, 14.25 Hz); 4.45 (s, 1H); 6.91 (dd, 1H, J=2.25, 8.68 Hz); 7.04 (d, 1H, J—1.87 Hz); 7.51 (d, 1H, J=5.17 Hz),
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH3:12][S:13]([O-:15])=[O:14].[Na+].[CH2:17]=O>O>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[CH2:12][S:13]([CH3:17])(=[O:15])=[O:14]
Reactant: Oc1ccnc2ccccc12
Reactant: CS(=O)[O-]
Reactant: C=O
Agent: [Na+]
Solvent: O
Product: CS(=O)(=O)Cc1cnc2ccccc2c1O
Reaction time: 24 h

Procedure:
A mixture of 4-hydroxyquinoline (2.9 g.), sodium methanesulphinate (8.16 g.), 40% aqueous formaldehyde (4.5 ml.) and water (70 ml.) was stirred at 95°-100° for 24 hours. More formaldehyde solution (5 ml.) was added and the mixture stirred at 95°-100° for a further 24 hours. The mixture was cooled and filtered to give the novel 4-hydroxy-3-methylsulphonylmethylquinoline, m.p. 280°-282° (from industrial methylated spirit:water).
Reaction SMILES: C([CH:3]([NH:8][C:9](=[O:26])[C@H:10]([CH2:22][CH:23]([CH3:25])[CH3:24])[NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH2:4][CH2:5][CH2:6][CH3:7])=O.[Cl-].[OH:28][NH3+].[N:30]1[CH:35]=CC=CC=1>C(O)C>[OH:28][N:30]=[CH:35][N:8]([CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[C:9](=[O:26])[C@H:10]([CH2:22][CH:23]([CH3:24])[CH3:25])[NH:11][C:12]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:13]
Reactant: CCCCC(C=O)NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Reactant: [NH3+]O
Reactant: c1ccncc1
Agent: [Cl-]
Solvent: CCO
Product: CCCCCN(C=NO)C(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1

Procedure:
In 15 ml of ethanol was dissolved 1.0 g of N-benzyloxycarbonyl-L-leucine-(1-formyl)pentylamide obtained in the same manner as in Example 4-(b), and 210 mg of hydroxyammonium chloride and 5 ml of pyridine were added thereto. The mixture was allowed to react at room temperature for 24 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure, and the residue was purified by medium-pressure column chromatography on silica gel to obtain 830 mg of the titled compound as a colorless crystal.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:14]2[CH:13]=[C:12](B(O)O)[CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[Br:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[C:25](Br)[CH:26]=2)[CH:21]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>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.O.C(COC)OC>[Br:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[CH:26]=[C:25]([C:12]1[CH:11]=[CH:10][C:9]3[C:8]4[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=4)[C:2]([CH3:1])([CH3:18])[C:14]=3[CH:13]=1)[CH:24]=[CH:23]2
Reactant: CC1(C)c2ccccc2-c2ccc(B(O)O)cc21
Reactant: Brc1ccc2cc(Br)ccc2c1
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: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: COCCOC
Product: CC1(C)c2ccccc2-c2ccc(-c3ccc4cc(Br)ccc4c3)cc21
Temperature: 85 °C
Reaction time: 8 h
Yield: 42.3 %

Procedure:
16.65 g (69.9 mmol) of 9,9-dimethyl-9H-fluorene-2-ylboronic acid, 20.0 g (69.9 mmol) of 2,6-dibromonaphthalene, 4.04 g (3.50 mmol) of tetrakis(triphenylphosphine)palladium (0), 200 ml of toluene, 200 ml of dimethoxyethane and 106 g of a 2M sodium carbonate aqueous solution were combined under argon atmosphere, and the mixture was stirred at 85° C. for 8 hours and left standing overnight. Water was added to the reaction mixture, and the mixture was stirred at room temperature for one hour. The mixture was filtered, the filtrate was extracted with toluene, and the organic phase was washed with water and subsequently with a saturated saline solution. The liquid was dried on sodium sulfate, and then toluene was removed by distillation under reduced pressure. A brown oily substance which resulted was refined by silica gel chromatography to obtain 11.8 g (yield: 42.4%) of 2-(6-bromonaphthalene-2-yl)-9,9-dimethyl-9H-fluorene.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[NH:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][NH:27][C:28]3[S:29][CH:30]=[CH:31][N:32]=3)[CH2:21][CH2:20]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:40](Cl)(=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.O>ClC(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[NH:18][CH:19]2[CH2:20][CH2:21][N:22]([CH2:25][CH2:26][N:27]([C:28]3[S:29][CH:30]=[CH:31][N:32]=3)[C:40](=[O:47])[C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH2:23][CH2:24]2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(Cn2c(NC3CCN(CCNc4nccs4)CC3)nc3ccccc32)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(c1ccccc1)N(CCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1)c1nccs1
Reaction time: 8 h
Yield: 48 %

Procedure:
To a stirred mixture of 6.76 parts of 1-[(4-fluorophenyl)methyl]-N-[1-[2-(2-thiazolylamino)ethyl]-4-piperidinyl]-1H-benzimidazol-2-amine, 1.5 parts of N,N-diethylethanamine and 225 parts of trichloromethane was added dropwise a solution of 2.1 parts of benzoyl chloride in trichloromethane. Upon completion, stirring was continued overnight. The reaction mixture was poured into water. The layers were separated. The organic layer was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (96:4 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2,2'-oxybispropane and 2-propanone. The product was filtered off and dried, yielding 4 parts (48%) of N-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]-N-(2-thiazolyl)benzamide; mp. 155.9° C. (compound 100).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][CH2:8][N:7]([C:12](=[O:14])[CH3:13])[C:6]=2[CH:15]=1.Cl[C:17]1[N:22]=[C:21]([NH:23][C:24]2[C:33]([F:34])=[CH:32][C:31]([C:35]3[CH:36]=[N:37][N:38]([CH3:40])[CH:39]=3)=[CH:30][C:25]=2[C:26]([NH:28][CH3:29])=[O:27])[C:20]([Cl:41])=[CH:19][N:18]=1>>[C:12]([N:7]1[C:6]2[CH:15]=[C:2]([NH:1][C:17]3[N:22]=[C:21]([NH:23][C:24]4[C:33]([F:34])=[CH:32][C:31]([C:35]5[CH:36]=[N:37][N:38]([CH3:40])[CH:39]=5)=[CH:30][C:25]=4[C:26]([NH:28][CH3:29])=[O:27])[C:20]([Cl:41])=[CH:19][N:18]=3)[CH:3]=[CH:4][C:5]=2[O:11][CH2:10][CH2:9][CH2:8]1)(=[O:14])[CH3:13]
Reactant: CC(=O)N1CCCOc2ccc(N)cc21
Reactant: CNC(=O)c1cc(-c2cnn(C)c2)cc(F)c1Nc1nc(Cl)ncc1Cl
Product: CNC(=O)c1cc(-c2cnn(C)c2)cc(F)c1Nc1nc(Nc2ccc3c(c2)N(C(C)=O)CCCO3)ncc1Cl

Procedure:
2-[2-(9-Acetyl-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-2-ylamino)-5-chloro-pyrimidin-4-ylamino]-3-fluoro-N-methyl-5-(1-methyl-1H-pyrazol-4-yl)-benzamide was prepared from 1-(2-amino-7,8-dihydro-6H-5-oxa-9-aza-benzocyclohepten-9-yl)-ethanone and 2-(2,5-dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-5-(1-methyl-1H-pyrazol-4-yl)-benzamide in an analogous manner to Example 1410. Product isolated as a pale yellow solid (140 mg, 72%). m.p.=172-177° C.; LCMS (m/e) 565 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.85 (bs, 1H), 8.09 (s, 1H), 7.92 (s, 1H), 7.89-7.81 (m, 2H), 7.45 (s, 1H), 7.38 (d, 1H, J=11.5 Hz), 7.03-6.87 (m, 3H), 6.60-6.50 (m, 1H), 4.65-4.50 (m, 1H), 4.43-4.29 (m, 1H), 4.01 (s, 3H), 3.63-3.47 (m, 1H), 3.00 (d, 3H, J=4.8 Hz), 2.55-2.37 (m, 1H), 2.23-2.06 (m, 1H), 1.87 (s, 3H), 1.72-1.57 (m, 1H); 19F-NMR (CDCl3, 400 MHz) δ −111.
Reaction SMILES: C([O:3][C:4](=[O:29])[C:5]([CH3:28])=[CH:6][C:7]1[O:8][C:9]([C:12](=[O:27])[CH2:13][CH:14]([CH3:26])[CH2:15][CH2:16][CH2:17][CH:18]([CH3:25])[CH2:19][CH2:20][CH2:21][CH:22]([CH3:24])[CH3:23])=[CH:10][CH:11]=1)C.[OH-].[Na+].Cl>C(O)C.O>[CH3:28][C:5](=[CH:6][C:7]1[O:8][C:9]([C:12](=[O:27])[CH2:13][CH:14]([CH3:26])[CH2:15][CH2:16][CH2:17][CH:18]([CH3:25])[CH2:19][CH2:20][CH2:21][CH:22]([CH3:23])[CH3:24])=[CH:10][CH:11]=1)[C:4]([OH:29])=[O:3]
Reactant: CCOC(=O)C(C)=Cc1ccc(C(=O)CC(C)CCCC(C)CCCC(C)C)o1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(=Cc1ccc(C(=O)CC(C)CCCC(C)CCCC(C)C)o1)C(=O)O

Procedure:
A mixture of ethyl-2-methyl-3-[5-(1-oxo-3,7,11-trimethyldodecyl)-2-furanyl]-2-propenoate (20.2 g-0.05 mole) in 200 ml ethanol is heated to reflux, 100 ml of 1 N aqueous NaOH is added and the mixture is refluxed for 2 hours, cooled, diluted with water, acidified with 200 ml 1 N aqueous hydrochloric acid and extracted with ether. The ether layer is evaporated to dryness to give 2-methyl-3-[5-(1-oxo-3,7,11-trimethyldodecyl)-2-furanyl]-2-propenoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](O)([C:26]([F:29])([F:28])[F:27])[CH2:10][C:11]([C:13]2[CH:14]=[CH:15][C:16]([N:21]3[CH:25]=[N:24][CH:23]=[N:22]3)=[C:17]([CH:20]=2)[C:18]#[N:19])=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1.S(Cl)(Cl)=O.N1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:26]([F:27])([F:29])[F:28])=[CH:10][C:11]([C:13]2[CH:14]=[CH:15][C:16]([N:21]3[CH:25]=[N:24][CH:23]=[N:22]3)=[C:17]([CH:20]=2)[C:18]#[N:19])=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: N#Cc1cc(C(=O)CC(O)(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1-n1cncn1
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: N#Cc1cc(C(=O)C=C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1-n1cncn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.1 %

Procedure:
After adding 3.00 g of toluene to 1.00 g (2.19 mmol) of 5-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutanoyl)-2-(1H-1,2,4-triazol-1-yl)benzonitrile, 0.52 g (4.39 mmol) of thionyl chloride and 0.35 g (4.39 mmol) of pyridine were added at 80° C., and stirred for 2 hours. The reaction solution was cooled to room temperature, and separated by adding 20 ml of ethyl acetate and 10 ml of water. After washing the ethyl acetate phase with an aqueous solution of 0.18 g of sodium hydroxide dissolved into 10 ml of water, the phase was washed with water. The solvent was distilled off under reduced pressure to obtain 0.92 g of 5-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-butenoyl)-2-(1H-1,2,4-triazol-1-yl)benzonitrile (yield 99.4%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][CH:17]([F:19])[F:18])[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1CCOCC1)C.[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.[CH2:50]([O:54][C:55]([N:57]1[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]1)=[O:56])[CH2:51][CH2:52][CH3:53]>C(OCC)(=O)C>[CH2:50]([O:54][C:55]([N:57]1[CH2:62][CH2:61][N:60]([C:13](=[O:15])[C@@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:16][CH:17]([F:19])[F:18])[CH2:59][CH2:58]1)=[O:56])[CH2:51][CH2:52][CH3:53]
Reactant: O=C(N[C@@H](CC(F)F)C(=O)O)OCc1ccccc1
Reactant: CCCCOC(=O)N1CCNCC1
Agent: CCN1CCOCC1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Product: CCCCOC(=O)N1CCN(C(=O)[C@H](CC(F)F)NC(=O)OCc2ccccc2)CC1
Reaction time: 12 h

Procedure:
To a solution of 114 mg (S)-2-Benzyloxycarbonylamino-4,4-difluoro-butyric acid were added 0.11 ml N-ethylmorpholine, 138 mg TOTU and 78 mg 1-butoxycarbonylpiperazine. After stirring for 12 h the reaction mixture was diluted with ethyl acetate and washed with aqueous LiCl (4%), 0.1 M HCl, saturated aqueous NaHCO3 and brine. The crude product obtained was used without further purification. Yield: 150 mg