Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:7]#[C:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[S:5][CH:6]=1.[C:15]([Li])(C)(C)C.IC>C1COCC1.CCCCC>[C:9]1([C:8]#[C:7][C:4]2[S:5][C:6]([CH3:15])=[CH:2][N:3]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Brc1csc(C#Cc2ccccc2)n1
Reactant: [Li]C(C)(C)C
Solvent: CI
Solvent: CCCCC
Solvent: C1CCOC1
Product: Cc1cnc(C#Cc2ccccc2)s1
Temperature: -78 °C

Procedure:
4-Bromo-2-(phenylethynyl)-1,3-thiazole (500 mg, 1.89 mmol) was dissolved in dry THF (10 mL) under argon, cooled to −78° C., then t-butyllithium (1.7 mL of a 1.7M solution in pentane, 2.8 mmol) was added. After 30 min 0.4 mL of the reaction mixture was quenched with saturated NH4Cl and extracted with ethyl acetate. GC/MS of the crude product from this workup and comparison with a GC/MS of authentic 2-(2-phenylethynyl)-thiazole showed the two to be identical. This confirmed that the initial coupling with phenylacetylene (in Example 9) took place at the bromine at the 2 position rather than at the 4 position. The GC/MS also showed that the reaction was not complete. Additional t-butyllithium (1.7 mL of a 1.7M solution in pentane, 2.8 mmol) was added. After 30 minutes iodomethane (0.36 mL, 5.7 mmol) was added to the reaction mixture, and the reaction was allowed to warm to ambient temperature for 16 h. The solvents were then removed in vacuo, and residue dissolved in ethyl acetate (50 mL), washed with water (50 mL), brine (50 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography eluting with hexane, 99:1, 98:2, 97.5:2.5 hexane:ethyl acetate to afford 2-(2-phenylethynyl)-5-methyl-1,3-thiazole (90 mg). 1H NMR analysis of the material showed it to be impure, despite its apparent homogeneity by TLC analysis. The crude compound was dissolved in DMSO and purified by preparative HPLC with a 30 min gradient from 70:30 water:acetonitrile to 100% acetonitrile to afford pure 5-methyl-2-(phenylethynyl)-1,3-thiazole as a white powder (44 mg, 24% yield). M.p. 82–83° C. 1H NMR (CDCl3, 300 MHz) δ 7.85–7.55 (m, 2H), 7.49 (d, J=0.6 Hz, 1H), 7.37–7.32 (m, 3H), 2.49 (s, 3H). MS (ESI) 200.1 (M++H).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([C:15]2[N:16]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[CH:17]=[C:18]([C:20]#[N:21])[N:19]=2)=[O:14])=[C:8]([C:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]=2)[CH:7]=1)[CH2:4][NH2:5].CS[C:38](SC)=[N:39][C:40]#[N:41]>C(Cl)Cl>[C:40]([N:39]=[C:38]1[NH:1][CH2:2][CH:3]([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13]([C:15]3[N:16]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:27])[CH3:28])[CH:17]=[C:18]([C:20]#[N:21])[N:19]=3)=[O:14])=[C:8]([C:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]=3)[CH:7]=2)[CH2:4][NH:5]1)#[N:41]
Reactant: CSC(=NC#N)SC
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(C(CN)CN)cc1C1=CCCCC1
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(C2CNC(=NC#N)NC2)cc1C1=CCCCC1
Temperature: 25 °C
Yield: 62 %

Procedure:
To a solution of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid [4-(2-amino-1-aminomethyl-ethyl)-2-cyclohex-1-enyl-phenyl]-amide (as prepared in the previous step, 15 mg, 0.030 mmol) in DCM (10 mL), dimethyl N-cyanodithioiminocarbonate (4.2 mg, 0.28 mmol) was added. The resulting solution was heated at reflux for 4 h. The reaction mixture was allowed to cool to RT and was concentrated in vacuo. The residue obtained was purified on silica (20-100% EtOAc-hexane) to obtain the title compound (11 mg, 62%): Mass spectrum (ESI, m/z): Calcd. for C28H36N8O2Si, 545.3 (M+H). found 545.1.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:19].C(OC([NH:27][CH:28]1[CH2:32][CH2:31][NH:30][CH2:29]1)=O)(C)(C)C.N12CCCN=C1CCCCC2>C(#N)C>[NH2:27][CH:28]1[CH2:32][CH2:31][N:30]([C:2]2[N:11]=[C:10]3[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]3[CH:12]3[CH2:14][CH2:13]3)=[CH:4][C:3]=2[F:19])[CH2:29]1
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: O=C(O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: NC1CCN(c2nc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)C1
Temperature: 60 °C
Reaction time: 1 h
Yield: 97.8 %

Procedure:
A suspension of 5.65 g (20 mmole) of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, 4.65 g (25 mmole) of 3-t-butoxycarbonylaminopyrrolidine, 7.9 g (50 mmole) of 1,8-diazabicyclo[5.4.0]undec-7-ene and 150 ml of acetonitrile was stirred at 60° C. for one hour. The solvent was removed in vacuo and the residue was dissolved in 100 ml of trifluoroacetic acid. After stirring at room temperature for one hour, the solvent was removed in vacuo and the residue was suspended in water and the pH adjusted to 11.5 with 50% sodium hydroxide. After filtering through a fiber glass pad to clarify, the filtrate was acidified to 6.6 with 6 M hydrochloric acid. The resulting precipitate was removed by filtration, washed with water, 2-propanol, ether and dried in vacuo to give 6.5 g (98%) of the title compound, mp 284°-286° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[C:21](Cl)=[N:20][CH:19]=[CH:18][N:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:23][O-:24].[Na+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[C:21]([O:24][CH3:23])=[N:20][CH:19]=[CH:18][N:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CNc2nccnc2Cl)CC1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nccnc1NCC1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
4-[(3-Chloro-pyrazin-2-ylamino)-methyl]-piperidine-1-carboxylic acid tert-butyl ester (3.0 g, 0.0092 mol) and 0.5M sodium methoxide in methanol (40 mL) were heated under nitrogen at 75° C. for 18 h. The reaction was concentrated in vacuo, diluted with methylene chloride (100 mL) and washed with water (pH=9, adjusted with NaOH). The organic extract was dried over sodium sulfate filtered and concentrated to give the title compound. M.S.(M+1): 323.
Reaction SMILES: [CH:1]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][CH:4]=[C:3]([OH:10])[CH:2]=1.C(N(CC)CC)C.Cl[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)=[O:20].O>O1CCCC1>[N+:29]([C:26]1[CH:25]=[CH:24][C:23]([CH2:22][O:21][C:19](=[O:20])[O:10][C:3]2[CH:4]=[CH:5][C:6]([N+:7]([O-:9])=[O:8])=[CH:1][CH:2]=2)=[CH:28][CH:27]=1)([O-:31])=[O:30]
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.1 %

Procedure:
To an ice cooled solution, under argon, of 7.3 g of p-nitrophenol and 7.5 ml of triethylamine in 36 ml of dry tetrahydrofuran, is added, dropwise, a solution of 10.78 g of p-nitrobenzyl chloroformate in 18 ml of dry tetrahydrofuran. The reaction mixture, a suspension, is stirred at room temperature overnight. The formed solid is collected,washed with water and dried to give 5.9 g of the desired product.
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].[CH3:7]O.C=O.[CH2:11]([NH:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH3:12]>CCCCC>[CH2:11]([N:13]([CH2:7][O:4][CH3:1])[CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH3:12]
Reactant: CCNC[Si](C)(C)C
Reactant: O=C([O-])[O-]
Reactant: CO
Agent: C=O
Agent: [K+]
Solvent: CCCCC
Product: CCN(COC)C[Si](C)(C)C
Temperature: -5 °C
Reaction time: 0.5 h

Procedure:
18.0 g (0.13 mol) of potassium carbonate, 121.8 g (3.80 mol) of methanol and 60.0 g (2.00 mol) of paraformaldehyde are initially charged and cooled to −5° C. At this temperature, within 30 min, 262.6 g (2.00 mol) of ethyltrimethylsilanylmethylamine are metered in. The biphasic reaction mixture is stirred at −5° C. for a further 1 h and then warmed to room temperature within 20 min. Within 1 min, 382 g of pentane are metered in. The biphasic reaction mixture is separated and the upper, organic phase is dried azeotropically for 2 h. The organic phase is concentrated and then fractionally distilled. Yield 228.5 g (71%) of a colorless liquid.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:13](=O)[CH3:14])=[CH:7]2.C([O-])(=O)C.[NH4+].C([BH3-])#[N:22].[Na+]>CO>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH:13]([NH2:22])[CH3:14])=[CH:7]2
Reactant: CC(=O)c1ccc2c(F)cc(F)cc2c1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CC(N)c1ccc2c(F)cc(F)cc2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 41.3 %

Procedure:
The above ketone (760 mg, 3.689 mmol) was dissolved in methanol (40 ml). Then, ammonium acetate (2.841 g, 36.896 mmol), sodium cyanoborohydride (232 mg, 3.389 mmol) and molecular sieves (3 Å, 7.6 g) were added. The mixture was stirred at room temperature for two days. The solid was filtered and the filtrate was concentrated. The residue was dissolved in water and concentrated aqueous HCl was added dropwise until the pH ≈2. The mixture was then extracted with ethyl acetate to remove the unfinished ketone and other by-products. The water layer was basified to pH≈10 with aqueous sodium hydroxide (1M), and was extracted with dichloromethane and the organic layers were combined, dried over magnesium sulfate and concentrated to afford 290 mg of 1-(5,7-difluoro-naphthalen-2-yl)-ethylamine (38% yield).
Reaction SMILES: [F:1][C:2]1([F:8])[CH2:4][CH:3]1[C:5](O)=[O:6].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:42]([O:44][C:45]([N:47]1[CH2:52][CH2:51][N:50]([C:53](=[O:88])[C@@H:54]([NH:58][C:59]([C:61]2[CH:65]=[C:64]([O:66][CH2:67][C:68]([N:70]3[CH2:74][CH2:73][CH2:72][C@H:71]3[C:75](=[O:81])[NH:76][CH:77]3[CH2:80][CH2:79][CH2:78]3)=[O:69])[N:63]([C:82]3[CH:87]=[CH:86][CH:85]=[CH:84][CH:83]=3)[N:62]=2)=[O:60])[CH2:55][CH2:56][NH2:57])[CH2:49][CH2:48]1)=[O:46])[CH3:43]>CN(C=O)C.ClCCl>[CH2:42]([O:44][C:45]([N:47]1[CH2:52][CH2:51][N:50]([C:53](=[O:88])[C@@H:54]([NH:58][C:59]([C:61]2[CH:65]=[C:64]([O:66][CH2:67][C:68]([N:70]3[CH2:74][CH2:73][CH2:72][C@H:71]3[C:75](=[O:81])[NH:76][CH:77]3[CH2:80][CH2:79][CH2:78]3)=[O:69])[N:63]([C:82]3[CH:87]=[CH:86][CH:85]=[CH:84][CH:83]=3)[N:62]=2)=[O:60])[CH2:55][CH2:56][NH:57][C:5]([CH:3]2[CH2:4][C:2]2([F:8])[F:1])=[O:6])[CH2:49][CH2:48]1)=[O:46])[CH3:43]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCN)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3ccccc3)n2)CC1
Reactant: O=C(O)C1CC1(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCNC(=O)C2CC2(F)F)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3ccccc3)n2)CC1
Reaction time: 12 h

Procedure:
To a solution of 19 mg 2,2-Difluorocyclopropane carboxylic acid in 3 ml DMF were added 0.03 ml DIPEA, 58 mg HATU and 100 mg 4-[(S)-4-Amino-2-({5-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester. After stirring for 12 h it was diluted with dichlormethane and extracted with aqueous LiCl (4% w/w), aqueous NaHCO3 and 0.1 M HCl. The crude product obtained after evaporation of the solvent was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA) to give the title compound. Yield: 55 mg MS (ES+): m/e=756.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:43])[N:4]=[C:5]([S:41][CH3:42])[C:6](=[N:24][C:25]1[CH:30]=[CH:29][C:28]([Br:31])=[C:27]([CH2:32][NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH:26]=1)[C:7]1[CH:12]=[C:11]([CH2:13][CH3:14])[CH:10]=[C:9]([O:15][Si](C(C)(C)C)(C)C)[C:8]=1[F:23].C1COCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>O>[CH3:1][O:2][C:3](=[O:43])[N:4]=[C:5]([S:41][CH3:42])[C:6](=[N:24][C:25]1[CH:30]=[CH:29][C:28]([Br:31])=[C:27]([CH2:32][NH:33][C:34]([O:36][C:37]([CH3:38])([CH3:39])[CH3:40])=[O:35])[CH:26]=1)[C:7]1[CH:12]=[C:11]([CH2:13][CH3:14])[CH:10]=[C:9]([OH:15])[C:8]=1[F:23]
Reactant: CCc1cc(O[Si](C)(C)C(C)(C)C)c(F)c(C(=Nc2ccc(Br)c(CNC(=O)OC(C)(C)C)c2)C(=NC(=O)OC)SC)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CCc1cc(O)c(F)c(C(=Nc2ccc(Br)c(CNC(=O)OC(C)(C)C)c2)C(=NC(=O)OC)SC)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 94.5 %

Procedure:
To a mixture of {2-[4-bromo-3-(t-butoxycarbonylaminomethyl)phenylimino)-2-[3-(t-butyldimethylsilanyloxy)-5-ethyl-2-fluorophenyl]-1-methylsulfanylethylidene}carbamic acid methyl ester (686 mg) and THF (25 mL) there was added a 1M THF solution (1.18 mL) of tetrabutylammonium fluoride at 0° C., under a nitrogen atmosphere. The mixture was stirred at 0° C. for 2 hours, and then ethyl acetate (200 mL) and water (100 mL) were added. The mixture was sufficiently shaken, and then the organic layer was separated off, washed twice with water (100 mL) and then with saturated aqueous sodium chloride (100 mL) in that order, and dried over anhydrous magnesium sulfate. The mixture was filtered to obtain a filtrate, and the solvent in the filtrate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane mixture) to obtain the target compound (542 mg) as a colorless solid.
Reaction SMILES: N1C=CC=CC=1.[Cl:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[Cl:16])[CH2:11]Br.[CH2:17]([O:19][C:20]([C@:22]1([NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[C@H:27]([NH2:28])[CH2:26][C@@H:25]2[C@H:23]1[C@@:24]2([F:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:21])[CH3:18].[Cl-].[Na+]>C(Cl)(Cl)Cl>[CH2:17]([O:19][C:20]([C@:22]1([NH:35][C:36]([O:38][C:39]([CH3:41])([CH3:40])[CH3:42])=[O:37])[C@H:27]([NH:28][CH2:11][C:10]2[CH:13]=[CH:14][C:15]([Cl:16])=[C:8]([Cl:7])[CH:9]=2)[CH2:26][C@@H:25]2[C@H:23]1[C@@:24]2([F:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:21])[CH3:18]
Reactant: Clc1ccc(CBr)cc1Cl
Reactant: CCOC(=O)[C@@]1(F)[C@@H]2C[C@@H](N)[C@@](NC(=O)OC(C)(C)C)(C(=O)OCC)[C@@H]21
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)[C@@]1(F)[C@@H]2C[C@@H](NCc3ccc(Cl)c(Cl)c3)[C@@](NC(=O)OC(C)(C)C)(C(=O)OCC)[C@@H]21
Temperature: 25 °C
Reaction time: 72 h
Yield: 39.3 %

Procedure:
42 μL of pyridine and 123 mg of 3,4-dichlorobenzylbromide were added to 175 mg of (1R,2R,3R,5R,6R)-3-amino-2-t-butoxycarbonylamino-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid diethyl ester dissolved in 0.88 mL of chloroform at ice-cooling, and the mixture was stirred for 3 days at room temperature. A saturated aqueous solution of sodium chloride was added thereto, and the mixture was extracted five times with chloroform. The organic layers were combined and then dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel: Wako gel C200, eluent:chloroform-ethanol=100:1 to 50:1, followed by hexane-ethyl acetate=5:1), thereby yielding 98 mg of (1R,2R,3R,5R,6R)-2-t-butoxycarbonylamino-3-(3,4-dichlorobenzylamino)-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid diethyl ester.
Reaction SMILES: [OH:1][C@@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@H:4]([CH3:8])[CH2:3]1.CCN(C(C)C)C(C)C.[F:34][C@@H:35]1[CH2:39][CH2:38][NH:37][CH2:36]1>>[OH:1][C@@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:37]4[CH2:38][CH2:39][C@@H:35]([F:34])[CH2:36]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@H:4]([CH3:8])[CH2:3]1
Reactant: C[C@H]1CCC[C@@](O)(CNC(=O)c2c(Cl)ccc3nc(Cl)ccc23)C1
Reactant: F[C@@H]1CCNC1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CCC[C@@](O)(CNC(=O)c2c(Cl)ccc3nc(N4CC[C@@H](F)C4)ccc23)C1

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid ((1S,3S)-1-hydroxy-3methyl-cyclohexylmethyl)-amide, DIPEA and (R)-3-fluoropyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.85 (m, 1H), 7.58 (2H), 7.05 (1H), 5.43-5.56 (1H), 4.16 (s, 1H), 3.89 (m, 2H), 3.70 (m, 1H), 3.55 (m, 1H), 3.26 (m, 2H), 2.44 (m, 2H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 5H), 1.27-1.32 (m, 1H), 0.83 (d, 3H). m/z: 420 [M+H]
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])C=C)=[CH:4][CH:3]=1.[F-].[Na+].[C:14](C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C.[F:30][C:31]([F:43])(S(F)(=O)=O)[C:32](O[Si](C)(C)C)=O>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:32]2[CH2:14][C:31]2([F:43])[F:30])=[O:11])=[CH:4][CH:3]=1
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: C[Si](C)(C)OC(=O)C(F)(F)S(=O)(=O)F
Reactant: C=CC(=O)c1ccc(Cl)cc1
Agent: [F-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C(c1ccc(Cl)cc1)C1CC1(F)F
Reaction time: 0.08 h

Procedure:
Under argon, 91 g (546 mmol) of 1-(4-chlorophenyl)prop-2-en-1-one, 2.293 g (54.6 mmol) of sodium fluoride and 2.41 g (10.92 mmol) of 2,6-di-tert-butyl 4-methylphenol were heated in a 3 liter three-necked flask to 110° C. and stirred at this temperature for 5 min. At an internal temperature of 110°-125° C., 183 ml (928.5 mmol) of trimethylsilyl 2,2-difluoro-2-(fluorosulphonyl)acetate were then slowly added dropwise over a period of 30-35 min to the solution (careful: evolution of gas). After the addition and the evolution of gas had ended, the reaction solution was stirred for another 20 min. After cooling, the reaction mixture was taken up in several liters of ethyl acetate and extracted with saturated aqueous sodium bicarbonate solution. The phases were separated, the organic phase was then dried over magnesium sulphate and filtered and the filtrate was concentrated to dryness. The crude product obtained was purified by chromatography on silica gel (about 2 kg) (mobile phase cyclohexane/ethyl acetate 10:1). This gave 63 g of the target product (53% of theory).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:44]=[C:45]([F:47])[CH:46]=1)[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2[NH:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]2)=[CH:20][C:19]=1[NH:37][CH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1)=[O:17].[C:48](Cl)(=[O:52])[O:49][CH2:50][CH3:51]>O1CCCC1.ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:44]=[C:45]([F:47])[CH:46]=1)[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([C:48]([O:49][CH2:50][CH3:51])=[O:52])[N:10]=[C:9]2[NH:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:20][C:19]=1[NH:37][CH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1)=[O:17]
Reactant: CCOC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)Nc3n[nH]c4ccc(Cc5cc(F)cc(F)c5)cc34)c(NC3CCOCC3)c2)CC1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOC(=O)n1nc(NC(=O)c2ccc(N3CCNCC3)cc2NC2CCOCC2)c2cc(Cc3cc(F)cc(F)c3)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl 4-[4-{[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]carbamoyl}-3-(tetrahydro-2H-pyran-4-ylamino)phenyl]piperazine-1-carboxylate (0.013 mmol) in anhydrous tetrahydrofurane (1.0 mL) maintained at −50° C. under argon atmosphere a 1M solution of LiHMSD in anhydrous tetrahydrofurane (0.015 mL) was added. After stirring at that temperature for 5 minutes ethyl chlorocarbonate (0.002 mL, 1.63 mg, 0.015 mmol) was added. After 30 minutes at −50° C. the reaction was completed. After diluting with dichloromethane, the solution was washed with brine, dried over sodium sulphate and evaporated to dryness. The crude was dissolved in dichloromethane (1 mL), trifluoroacetic acid (0.1 mL) was added and the mixture was stirred at room temperature overnight. After diluting with dichloromethane, the solution was washed with sodium hydrogencarbonate, with brine, dried over sodium sulphate and evaporated to dryness.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1/[CH:11]=[C:12](\[CH3:18])/[C:13]([O:15][CH2:16][CH3:17])=[O:14].[Cl-].[NH4+]>O1CCCC1.CO.[Fe]>[F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1/[CH:11]=[C:12](\[CH3:18])/[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)/C(C)=C/c1ccc([N+](=O)[O-])cc1F
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)/C(C)=C/c1ccc(N)cc1F
Yield: 85.2 %

Procedure:
Compound 14c (17.3 g) was dissolved in tetrahydrofuran (180 ml) and methanol (180 ml), and iron powder (19.1 g) was added thereto. An ammonium chloride aqueous solution (1.67 mol/l, 110 ml) was added to the reaction mixture while refluxing under heating. The obtained mixture was refluxed under heating for 1 hour. After the mixture was allowed to cool, the iron powder was removed by Cerite filtration. Ethyl acetate and purified water were added to the filtrate, and extraction and washing were carried out. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was recrystallized with n-heptane to obtain Compound 14d (13.0 g, 85%) as an opalescent solid.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][N:5]([C:7]2[CH:8]=[N:9][C:10]([Cl:14])=[C:11]([Cl:13])[CH:12]=2)[CH2:4][C@@H:3]1[CH2:15]O.S(Cl)(Cl)=O.CN1CCCC1=O.[OH-].[Na+]>COCCOC>[Cl:13][C:11]1[CH:12]=[C:7]([N:5]2[CH2:6][C@@H:2]3[C@@H:3]([CH2:15][NH:1]3)[CH2:4]2)[CH:8]=[N:9][C:10]=1[Cl:14]
Reactant: N[C@@H]1CN(c2cnc(Cl)c(Cl)c2)C[C@@H]1CO
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Solvent: CN1CCCC1=O
Solvent: O=S(Cl)Cl
Product: Clc1cc(N2C[C@@H]3CN[C@@H]3C2)cnc1Cl

Procedure:
The treatment of Compound 6E with an acid such as hydrochloric acid under cooling conditions provides (allyl-5,6-dichloro-pyridin-3-yl)-amino)-acetaldehyde which when treated with 2-(S)-hydroxyamino-2-phenyl-ethanol and magnesium bromide in a solvent such as isopropyl alcohol provides (3S,4S)-2-[5-(5,6-dichloro-pyridin-3-yl)-hexahydro-pyrrolo[3,4-c]isoxazol-1-yl]-2-(2′S)-phenyl-ethanol (Compound 6H). Compound 6H when treated with methanesulfonyl chloride to generate the mesylate which is then treated with sodium tert-butoxide followed by an acidic workup provides (3S,4S)-5-(5,6-dichloro-pyridin-3-yl)-hexahydro-pyrrolo[3,4-c]isoxazole (Compound 6I). The treatment of Compound 6I with Raney-nickel and 40 PSI of hydrogen in a mixture of tetrahydrofuran, ethanol and water provides (3S,4S)-[4-amino-1-(5,6-dichloro-pyridin-3-yl)-pyrrolidin-3-yl]-methanol (Compound 6J). The treatment of Compound 6J with thionyl chloride and N-methylpyrrolidinone under heated conditions in 1.2-dimethoxyethane followed by treatment with sodium hydroxide or another similar base provides (1S, 5S)-3-(5,6-dichloropyridin-3-yl)-3,6-diaza-bicyclo[3.2.0]heptane (Compound 6K).
Reaction SMILES: [CH3:1][CH:2]1[S:6][C:5]([NH:7][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])[CH3:9])=[N:4][C:3]1=[O:17].Br[C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=1.CC1(C2C=CC(C#N)=CC=2)SC(N[C@H](C2C=CC=CC=2C(F)(F)F)C)=NC1=O>>[F:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C@@H:8]([NH:7][C:5]1[S:6][C:2]([C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=2)([CH3:1])[C:3](=[O:17])[N:4]=1)[CH3:9]
Reactant: CC1SC(N[C@@H](C)c2ccccc2F)=NC1=O
Reactant: N#Cc1ccc(Br)cc1
Agent: C[C@H](NC1=NC(=O)C(C)(c2ccc(C#N)cc2)S1)c1ccccc1C(F)(F)F
Product: C[C@H](NC1=NC(=O)C(C)(c2ccc(C#N)cc2)S1)c1ccccc1F

Procedure:
The title compound was prepared from the reaction of 5-methyl-2-((S)-1-(2-fluorophenyl)ethylamino)thiazol-4(5H)-one with 4-bromobenzonitrile using the procedure described for 2a. MS (ESI, pos. ion) m/z: 354 (M+1).