Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[CH2:3](COC)[O:4]C.[F:9][C:10]1[C:18]([F:19])=[C:17](C(O)=O)[C:16]([F:23])=[C:15]([F:24])[C:11]=1[C:12]([OH:14])=O.Cl>O.C1(C)C=CC=CC=1>[F:24][C:15]1([CH2:3][OH:4])[C:16]([F:23])=[CH:17][C:18]([F:19])=[C:10]([F:9])[CH:11]1[CH2:12][OH:14]
Reactant: O=C(O)c1c(F)c(F)c(C(=O)O)c(F)c1F
Reactant: COCCOC
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: OCC1C(F)=C(F)C=C(F)C1(F)CO
Temperature: 50 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
Into a 200 mL flask equipped with a reflux condenser, 2.58 g of sodium borohydride and 25 g of dimethoxyethane were charged. The obtained mixture was adjusted to 50° C. and then, a solution obtained by mixing 6.10 g of 2,3,5,6-tetrafluoroterephthalic acid with 20 g of dimethoxyethane was added dropwise thereto over 1 hour while stirring. The obtained mixture was stirred for 7 hours at 60° C. To the obtained reaction mixture, 20 g of toluene was added followed by cooling to 50° C. Eight point five grams of 35% by weight hydrochloric acid was added dropwise thereto over 1 hour to stir at 60° C. for 6 hours. To the obtained mixture, 30 g of water was added followed by separating to an organic layer and an aqueous layer. The aqueous layer was extracted twice with 30 g of ethyl acetate. The obtained organic layers were mixed and washed with 10 g of a saturated aqueous potassium carbonate solution and then with 10 g of water. The organic layer was concentrated and the obtained solids were recrystallized with toluene and hexane to obtain white powder crystals of 2,3,5,6-tetrafluorobenzenedimethanol. The crystals were analyzed by liquid chromatography absolute calibration curve method to find out that the purity thereof was 95.1%. Yield: 95%.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([Cl:13])[CH:3]=1.[F:14][C:15]1[CH:21]=[C:20]([I:22])[CH:19]=[CH:18][C:16]=1[NH2:17]>CCO.Cl>[Cl:13][C:4]1[CH:3]=[C:2]([NH:17][C:16]2[CH:18]=[CH:19][C:20]([I:22])=[CH:21][C:15]=2[F:14])[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=1
Reactant: CCOC(=O)c1cnc(Cl)cc1Cl
Reactant: Nc1ccc(I)cc1F
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cnc(Cl)cc1Nc1ccc(I)cc1F
Temperature: 90 °C

Procedure:
Ethyl 4,6-dichloronicotinate [prepared according to the literature procedure of J. Chem. Soc. 5163 (1963)] (4.00 g, 18.2 mmol) and 2-fluoro-4-iodoaniline (4.30 g, 18.2 mmol) were dissolved in EtOH (80 mL), to which was added conc. HCl (6 drops). This mixture was heated, in an oil bath at 90° C., for 15 h. The solution was allowed to cool, then refrigerated whereupon the desired product crystallised out of solution as fine needles. The product was isolated by filtration and washed with 10% Et2O/hexanes to give ethyl 6-chloro-4-(2-fluoro-4-iodoanilino)nicotinate as white needles (3.79 g, 50%), m.p. (EtOAc/n-hexane) 162-164° C. 1H NMR [(CD3)2SO, 400 MHz] δ 9.62 (s, 1H), 8.69 (s, 1H), 7.82 (dd, J=9.9, 1.9 Hz, 1H), 7.61-7.66 (m, 1H), 7.33 (t, J=8.5 Hz, 1H), 6.67 (d, J=1.8 Hz, 1H), 4.37 (q, J=7.1 Hz, 2H), 1.35 (t, J=7.1 Hz, 3H). Anal. Calcd for C14H11ClFIN2O2: C, 40.0; H, 2.6; N, 6.7. Found: C, 40.3; H, 2.2; N, 6.7.
Reaction SMILES: C([N:11]1[CH2:18][C@@H:17]2[C@@H:13]([CH2:14][N:15]([C:19]3[CH:24]=[CH:23][C:22]([N:25]4[CH2:29][C@H:28]([CH2:30][NH:31][C:32](=[O:34])[CH3:33])[O:27][C:26]4=[O:35])=[CH:21][C:20]=3[F:36])[CH2:16]2)[CH2:12]1)(OCC1C=CC=CC=1)=O.C(Cl)Cl>[Pd].CO>[C@@H:17]12[CH2:16][N:15]([C:19]3[CH:24]=[CH:23][C:22]([N:25]4[CH2:29][C@H:28]([CH2:30][NH:31][C:32](=[O:34])[CH3:33])[O:27][C:26]4=[O:35])=[CH:21][C:20]=3[F:36])[CH2:14][C@@H:13]1[CH2:12][NH:11][CH2:18]2
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3C[C@H]4CN(C(=O)OCc5ccccc5)C[C@H]4C3)c(F)c2)C(=O)O1
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2ccc(N3C[C@H]4CNC[C@H]4C3)c(F)c2)C(=O)O1

Procedure:
(S)-N-[[3-[4-[cis-3-(Carbobenzyloxy)-3,7-diazabicyclo[3.3.0]octan-7-yl]-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (150 mg, 0.30 mmol), methylene chloride (5 mL), and methanol (10 mL) are combined with 10% palladium on carbon (30 mg) and placed under a hydrogen atmosphere (balloon) for 15 hours. The reaction is filtered through celite and concentrated in vacuo to give crude (S)-N-[[3-[4-[cis- 3,7-diazabicyclo[3.3.0]octan-7-yl]-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide. To the crude (S)-N-[[3-[4-[cis-3,7-diazabicyclo[3.3.0]octan-7-yl]-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (115 mg, 0.30 mmol) dissolved in pyridine (5 mL) at 0° C. is added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (70 mg, 0.35 mmol), 4-dimethylaminopyridine (5 mg, 0.05 mmol), and isoxazole-5-carboxylic acid (40 mg, 0.35 mmol). The reaction is warmed to ambient temperature, stirred 15 hours, diluted with methylene chloride (30 mL). The organic phase is washed with 1N HCl (20 mL) and saline (20 mL), dried over sodium sulfate, concentrated in vacuo, and chromatographed on silica gel (230-400 mesh, 100 mL), eluting with chloroform/methanol (97/3). The appropriate fractions are combined (Rf =0.16, TLC, chloroform/methanol, 95/5) and concentrated in vacuo to give the title compound, mp 172-175° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:9])[C:7]=1Cl.[C:10]([CH:12]1[CH2:16][CH2:15][NH:14][CH2:13]1)#[N:11].C(N(CC)CC)C>CN1C(=O)CCC1>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:9])[C:7]=1[N:14]1[CH2:15][CH2:16][CH:12]([C:10]#[N:11])[CH2:13]1
Reactant: Clc1c(Br)cncc1Br
Reactant: N#CC1CCNC1
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: N#CC1CCN(c2c(Br)cncc2Br)C1

Procedure:
General procedure C was followed using 3,5-dibromo-4-chloropyridine (71 mg, 0.26 mmol), 3-cyanopyrrolidine (25 mg, 0.26 mmol), NMP (3 mL) and triethylamine (72 μL, 0.52 mmol). The crude product was purified by flash column chromatography on silica gel (CH2Cl2, MeOH, 99:1) to furnish the title compound E22 as a white solid (9 mg, 10%), m.p. 159-161° C.; umax (CHCl3)/cm−1 3022, 3008, 1678, 1591, 1446, 1235; m/z (ESI) C10H12Br2N3O requires 347.9342, found [M+H]+ 347.9339.
Reaction SMILES: [C:1]1([C:7]2([CH2:16][CH2:17][C:18]#[N:19])[CH2:12][CH2:11][CH2:10][CH:9]([CH:13]=[O:14])[C:8]2=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C2(CCC#N)CCCC[C:27]2=[O:32])C=CC=CC=1.C(OC=O)C>>[CH3:27][O:32][C:5]1[CH:6]=[C:1]([C:7]2([CH2:16][CH2:17][C:18]#[N:19])[CH2:12][CH2:11][CH2:10][CH:9]([CH:13]=[O:14])[C:8]2=[O:15])[CH:2]=[CH:3][CH:4]=1
Reactant: N#CCCC1(c2ccccc2)CCCCC1=O
Reactant: N#CCCC1(c2ccccc2)CCCC(C=O)C1=O
Solvent: CCOC=O
Product: COc1cccc(C2(CCC#N)CCCC(C=O)C2=O)c1

Procedure:
Following the procedure set forth in Example 1 there was prepared 2-phenyl-2-(2-cyanoethyl)-6-formylcyclohexanone from 2-phenyl-2-(2-cyanoethyl)cyclohexanone and ethylformate.
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]([NH2:6])=[S:5].[C:7]1([N:13]=[C:14]=[S:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl>O.CC#N>[C:7]1([NH:13][C:14]([NH:3][C:4]([NH2:6])=[S:5])=[S:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: S=C=Nc1ccccc1
Reactant: NC(N)=S
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: NC(=S)NC(=S)Nc1ccccc1
Temperature: 40 °C
Reaction time: 8 h
Yield: 28.2 %

Procedure:
To a stirring solution of NaOH (0.52 g, 13.1 mmol) in 60 mL of 10% H2O:CH3CN was added thiourea (1.0 g, 13.1 mmol). The resulting suspension was heated to 40° C. for 20 min. and then cooled to RT. To this mixture was added phenylisothiocyanate (1.5 ml, 13.1 mmol), and the clear yellow solution was stirred overnight. After stirring for 12 h, 1 N HCl was added until a white precipitate formed. The precipitate was filtered, washed with H2O, and dried under vacuum to produce the title compound as a light yellow powder (0.78 g, 30%). 1H-NMR (400 MHz, d6-DMSO) δ7.25 (t, 2H, J=7.3 Hz), 7.40 (t, 2H, J=7.9 Hz), 7.56 (d, 1H, J=7.9 Hz), 9.13-9.29 (broad singlet, 1H), and 10.26-10.79 (broad singlet, 2H).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]([NH2:18])[N:13]=3)=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:22]=[C:23]([N:27]=[C:28]=[O:29])[CH:24]=[CH:25][CH:26]=1>C1COCC1>[F:19][C:20]([F:30])([F:31])[C:21]1[CH:22]=[C:23]([NH:27][C:28]([N:1]2[C:10]3[C:5](=[CH:6][C:7]([O:11][C:12]4[CH:17]=[CH:16][N:15]=[C:14]([NH2:18])[N:13]=4)=[CH:8][CH:9]=3)[CH2:4][CH2:3][CH2:2]2)=[O:29])[CH:24]=[CH:25][CH:26]=1
Reactant: Nc1nccc(Oc2ccc3c(c2)CCCN3)n1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Solvent: C1CCOC1
Product: Nc1nccc(Oc2ccc3c(c2)CCCN3C(=O)Nc2cccc(C(F)(F)F)c2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 242 mg (1 mmol) 4-(1,2,3,4-tetrahydro-quinolin-6-yloxy)-pyrimidin-2-ylamine (Step 29.2) in 5 mL of dry THF are added 205 mg (1.1 mmol) of 3-trifluoromethyl-phenylisocyanate at RT. The solution is stirred for 2 h at RT and then the THF is evaporated. The residue is purified by flash-chromatography on silica gel using dichloromethane/methanol 95:5 as eluent. Fractions with pure compound are pooled and evaporated to give the title compound as an amorphous material: MS: [M+1]+=430; HPLC: CtRet=2.14; TLC (dichloromethane/methanol 95:5): Rf=0.45.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH:14]=O)[CH:12]=2)[N:7]=[CH:6][N:5]=1)[CH3:2].[F:16][C:17]1[CH:18]=[C:19]([CH2:23][CH2:24][NH:25][C:26]2[S:27][CH2:28][C:29](=[O:31])[N:30]=2)[CH:20]=[CH:21][CH:22]=1.N1CCCCC1>C(O)C>[CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11](/[CH:14]=[C:28]3/[C:29](=[O:31])[N:30]=[C:26]([NH:25][CH2:24][CH2:23][C:19]4[CH:20]=[CH:21][CH:22]=[C:17]([F:16])[CH:18]=4)[S:27]/3)[CH:12]=2)[N:7]=[CH:6][N:5]=1)[CH3:2]
Reactant: O=C1CSC(NCCc2cccc(F)c2)=N1
Reactant: CCOc1ncnc2ccc(C=O)cc12
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOc1ncnc2ccc(/C=C3\SC(NCCc4cccc(F)c4)=NC3=O)cc12
Yield: 28.4 %

Procedure:
The mixture of 4-ethoxy-quinazoline-6-carbaldehyde (example 10b, 20 mg, 0.1 mmol,), 2-[2-(3-Fluoro-phenyl)-ethylamino]-thiazol-4-one (example 10c, 24 mg, 0.1 mmol) and piperidine (10 ul, 0.1 mmol) in anhydrous ethyl alcohol (1 ml) was microwaved at 160° C. for 25 min. After cooling the reaction to room temperature, the solid was collected by filtration, then washed with MeOH and dried to afford 5-[1-(4-ethoxy-quinazolin-6-yl)-meth-(Z)-ylidene]-2-[2-(3-fluoro-phenyl)-ethylamino]-thiazol-4-one (12 mg, 30%) as light yellow solid. LC-MS m/e 423 (MH+).
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[Cl:10][C:11]1[N:16]=[CH:15][N:14]=[C:13]([CH:17](O)[CH3:18])[CH:12]=1>C(Cl)Cl>[Cl:10][C:11]1[CH:12]=[C:13]([CH:17]([F:7])[CH3:18])[N:14]=[CH:15][N:16]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(O)c1cc(Cl)ncn1
Solvent: ClCCl
Product: CC(F)c1cc(Cl)ncn1
Temperature: -78 °C
Reaction time: 4 h
Yield: 37.6 %

Procedure:
(Diethylamino)sulphur trifluoride (0.337 mL, 2.55 mmol) was added to DCM (13 mL), cooled to −78° C. and treated dropwise with a solution of 1-(6-chloro-4-pyrimidinyl)ethanol (Intermediate 20, 328 mg, 2.068 mmol) in DCM (4 mL) under argon. The resulting mixture was allowed to warm to room temperature and stirred for 4 hours. The reaction was quenched by adding water (5 mL) and extracted with DCM (×2). The DCM layers were separated, combined, dried under magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (Biotage SP4) eluting with a gradient of 0-25% ethyl acetate and iso-hexane. Product containing fractions were combined and evaporated under reduced pressure to give the title compound as a colourless oil (125 mg);
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH:4]([C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[C:14]([Br:21])[CH:13]=1)C(OC(C)(C)C)=O.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:22])[CH2:4][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[C:14]([Br:21])[CH:13]=1
Reactant: COC(=O)C(C(=O)OC(C)(C)C)c1ccc([N+](=O)[O-])c(Br)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: COC(=O)Cc1ccc([N+](=O)[O-])c(Br)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 94.9 %

Procedure:
The 2-(3-bromo-4-nitrophenyl)malonic acid tert-butyl ester methyl ester (1.18 g) obtained in Example 4 a) was dissolved in chloroform (10 mL), trifluoroacetic acid (10 g) was added thereto under ice-cooling, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was poured gradually into ice and saturated aqueous sodium bicarbonate, and extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over sodium sulfate and concentrated to give the title compound (0.820 g) as a pale yellow oil.
Reaction SMILES: [C:1]1([C:7](=[N:14][CH:15]([CH2:18][CH2:19][F:20])[C:16]#[N:17])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:21]([Li])CCC.IC>C1COCC1>[C:1]1([C:7](=[N:14][C:15]([CH3:21])([CH2:18][CH2:19][F:20])[C:16]#[N:17])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [Li]CCCC
Reactant: N#CC(CCF)N=C(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CI
Product: CC(C#N)(CCF)N=C(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 96.4 %

Procedure:
19.94 g (63.64 mmol, 85% purity) of rac-2-[(diphenylmethylene)amino]-4-fluorobutanonitrile from Example 66A were initially charged in 421 ml of abs. THF, and 25.71 ml (64.28 mmol) of n-butyllithium (2.5 N in hexane) were added at −78° C. under argon, and the mixture was stirred at −78° C. for a further 10 min. Subsequently, 36.1 g (254.57 mmol) of iodomethane were added to the reaction solution at −78° C. The reaction mixture was gradually brought to 0° C. over 4.5 h. After complete depletion of the starting material, the reaction solution was quenched with water at 0° C., ethyl acetate was added and the mixture was washed twice with saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulphate, filtered and concentrated by rotary evaporation. The residue was purified by means of silica gel chromatography (eluent:cyclohexane/ethyl acetate=15/1). 17.2 g of the target compound were obtained (78% of theory, 81% purity).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[C:7]1[CH:12]=[CH:11][C:10]([N:13]=[N:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]Br)=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].O.O.O.O.O.[S:35]([O-])([O-])(=O)=S.[Na+].[Na+]>O.C(O)C>[C:1]([O:5][C:6](=[O:29])[C:7]1[CH:12]=[CH:11][C:10]([N:13]=[N:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][SH:35])=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)c1ccc(N=Nc2ccc(OCCCCCCBr)cc2)cc1
Reactant: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)c1ccc(N=Nc2ccc(OCCCCCCS)cc2)cc1
Temperature: 25 °C

Procedure:
4-[4-(6-Mercapto-hexyloxy)-phenylazo]-benzoic acid t-butyl ester was synthesized by modifying a literature procedure [Material Science and Engineering, 1999, 8-9, 385-389; J. Phys. Chem., 1995, 99, 7102]. 0.41 g (0.9 mmol) of 4-[4-(6-bromo-hexyloxy)-phenyazo]-benzoic acid t-butyl ester and 0.25 mg (1.1 mmol) of sodium thiosulfate pentahydrate in 5 mL of water was dissolved in 18 mL of ethanol and refluxed for 3 hours. The mixture was stirred at room temperature for an additional hour. After cooling, the precipitate was filtered off using a fritted funnel. A fine orange solid (bunte salt) was obtained and was used without purification. 10 ml of chloroform and 10 mL of 1M HCl were added to the bunte salt. The reaction mixture was refluxed for 2 hours at 70° C. after which the orange organic phase was extracted from the colorless aqueous layer. The organic layers were further extracted with 10 mL of chloroform (3 times) and combined, washed with saturated NaHCO3 solution, distilled water, and then dried over MgSO4. The solvent was removed by roto-evaporation and the product (compound 1, FIG. 11) was further purified by recrystallization from an ethanol-water mixture. Drying under vacuum produced a fine orange powder (0.22 g, 60% yield) with the following characteristics: 1H NMR (CDCl3) δ 8.11 (d, J=9 Hz, 2H), 7.91 (dd, J=9 Hz, 4H), 7.14 (d, J=9 Hz, 2H), 4.08 (t, J=6 Hz, 2H), 2.48 (m, 2H), 1.85-1.41 (m, 17H), 1.32 (t, 1H). High-resolution mass spectroscopy (HR-MS) yielded a mass of 414.1988 compared to the value 414.1628 calculated for C23H30O3N2S.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([O:6][CH:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.C([Li])CCC.[S:20](Cl)([Cl:23])(=[O:22])=[O:21]>O1CCCC1.CCCCCC>[O:10]1[CH2:11][CH2:12][CH:7]([O:6][C:5]2[CH:13]=[CH:14][C:2]([S:20]([Cl:23])(=[O:22])=[O:21])=[CH:3][CH:4]=2)[CH2:8][CH2:9]1
Reactant: O=S(=O)(Cl)Cl
Reactant: Brc1ccc(OC2CCOCC2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=S(=O)(Cl)c1ccc(OC2CCOCC2)cc1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of 2.8 g of 4-(4-Bromo-phenoxy)-tetrahydropyran in 75 mL of dry tetrahydrofuran was added 7.5 mL of n-butyllithium (1.6 N in hexane) at −78° C. After stirring at −78° C. for 2 hours the reaction mixture was allowed to warm to −40° C. and a solution of 4.1 mL of sulfuryl chloride in 75 mL of dry hexane was added within 15 minutes. Stirring was continued for 1 hour at −30° C. and subsequently for another hour at 5° C., The mixture was poured on ice, extracted with diethyl ether and the ether extract washed with cold water and brine, dried (sodium sulfate), and concentrated. The residue was purified by silica chromatography (isohexane/ethyl acetate=4/1) yielding 0.62 g of 4-(tetrahydropyran-4-yloxy)-benzenesulfonyl chloride as a colorless oil. EI-MS: 276 (M+).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:19][CH2:18][C:9]2[C:10]3[C:15](Cl)=[N:14][CH:13]=[N:12][C:11]=3[S:17][C:8]=2[CH2:7]1)=[O:5])[CH3:2].[Br:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24]>C(O)C.Cl>[Br:20][C:21]1[CH:22]=[C:23]([NH:24][C:15]2[C:10]3[C:9]4[CH2:18][CH2:19][CH:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:7][C:8]=4[S:17][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: Nc1cccc(Br)c1
Reactant: CCOC(=O)C1CCc2c(sc3ncnc(Cl)c23)C1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C1CCc2c(sc3ncnc(Nc4cccc(Br)c4)c23)C1
Temperature: 70 °C
Yield: 77.2 %

Procedure:
In a 25 mL round-bottom flask were placed 250 mg (0.84 mmol, 1.1 equiv) of 4-chloro-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidine-7-carboxylic acid ethyl ester and 131 mg (0.77 mmol, 1 equiv) m-bromoaniline in 10 mL of ethanol with one drop conc HCl. The flask was equipped with a reflux condenser and heated at 70° C. for 4 h. The mixture was allowed to cool to rt and ethanol was concentrated in vacuo. The resulting crude residue was re-dissolved in EtOAc (10 mL), poured into a separatory funnel and washed with satd NaHCO3 (1×10 mL). The organic layer was dried (MgSO4), filtered and concentrated to give a crude oil. The crude material was further purified by MPLC (Biotage) using 1/4 EtOAc/Hex to provide 257 mg (77%) of the desired product, 14, as a white powder. 1H-NMR (CDCl3-d) δ 8.44 (s, 1H), 7.92 (s, 1H), 7.55 (m, 1H), 7.23 (m, 2H), 7.08 (s, 1H), 4.22 (q, 2H), 3.14 (m, 4H), 2.91 (m, 1H), 2.39 (m, 1H), 2.14 (m, 1H), 1.30 (t, 3H); LCMS RT=3.48 min; [M+H]+=432.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8](Br)[CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1.[F:25][C:26]1[CH:51]=[CH:50][CH:49]=[CH:48][C:27]=1[CH2:28][N:29]1[C:37]([NH2:38])=[C:36]2[C:31]([CH:32]=[C:33](B3OC(C)(C)C(C)(C)O3)[CH:34]=[CH:35]2)=[N:30]1.C([O-])([O-])=O.[Na+].[Na+].O>CN(C=O)C.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>[NH2:1][C:2]1[C:7]2=[C:8]([C:33]3[CH:34]=[CH:35][C:36]4[C:31]([CH:32]=3)=[N:30][N:29]([CH2:28][C:27]3[CH:48]=[CH:49][CH:50]=[CH:51][C:26]=3[F:25])[C:37]=4[NH2:38])[CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(Br)c3c(N)ncnn23)CC1
Reactant: CC1(C)OB(c2ccc3c(N)n(Cc4ccccc4F)nc3c2)OC1(C)C
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: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2cc(-c3ccc4c(N)n(Cc5ccccc5F)nc4c3)c3c(N)ncnn23)CC1
Temperature: 110 °C

Procedure:
To a solution of tert-butyl 4-(4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidine-1-carboxylate (0.5 g, 1.26 mmol) in DMF (15 mL) was added 2-(2-fluorobenzyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazol-3-amine (0.695 g, 1.89 mmol), solid Na2CO3 (0.4 g, 3.79 mmol) and water (1.9 mL). The solution was degassed for 10 min and tetrakis(triphenylphosphine)palladium(0) (0.146 g, 0.126 mmol) was added and the mixture was degassed for another 10 min. The mixture was heated at 110° C. for 1 h 15 min and then cooled to rt. The mixture was filtered through a plug of Celite® and the filtrate was concentrated. The crude purified using an ISCO® instrument using 40-100% ethyl acetate in hexanes. LC-MS [M+H]+=557.2, RT=2.65 min.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:8]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:9]([C:11]2[CH:30]=[CH:29][C:14]3[N:15]([CH3:28])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.[ClH:38].C(O)C.C(=O)([O-])[O-].[NH4+:46].[NH4+]>ClCCl.C(O)C>[ClH:38].[CH3:1][C:2]1[CH:3]=[C:4]([N:8]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:9]([C:11]2[CH:30]=[CH:29][C:14]3[N:15]([CH3:28])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:46])[NH2:27])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: [NH4+]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C#N)cc1)n2C)c1cccc(C)c1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1cccc(C)c1
Yield: 79 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(3-methylphenyl)-N-(2-ethoxycarbonylethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 79% of theory, C29H32N6O3 (512.6) Rf value: 0.10 (silica gel; dichloromethane/ethanol=4:1) ##EQU59##
Reaction SMILES: [CH2:1]=[C:2]1[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4][CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O/[N:29]=[C:30](/[C:36]1[N:37]=[C:38]([NH:41][C:42]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[S:39][CH:40]=1)\[C:31]([O:33][CH2:34][CH3:35])=[O:32].N(C(OC)=O)=NC(OC)=O>C1C=CC=CC=1>[CH2:1]=[C:2]1[CH2:7][CH2:6][CH:5]([O:8]/[N:29]=[C:30](/[C:36]2[N:37]=[C:38]([NH:41][C:42]([C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)([C:49]3[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=3)[C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[S:39][CH:40]=2)\[C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:4][CH2:3]1
Reactant: CCOC(=O)/C(=N\O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: C=C1CCC(O)CC1
Agent: COC(=O)N=NC(=O)OC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: C=C1CCC(O/N=C(\C(=O)OCC)c2csc(NC(c3ccccc3)(c3ccccc3)c3ccccc3)n2)CC1
Reaction time: 65 h
Yield: 10.5 %

Procedure:
4-Methylenecyclohexanol (412 mg), triphenylphosphine (860 mg), and ethyl (Z)-2-hydroxyimino-2-(2-tritylaminothiazol-4-yl)acetate (1.37 g) were dissolved together in anhydrous benzene (9 ml). Dimethyl azodicarboxylate (0.40 ml) was added slowly with stirring and the resulting orange solution was stored at room temperature for 65 h with exclusion of moisture. Workup and chromatography as in example 4a, method 3 afforded the title compound (174 mg), δH (CDCl3) 1.33 (3H, t, J 7 Hz), 1.82, 2.08 and 2.31 (8H, 3m), 4.35 (2H, q, J 7 Hz), 4.51 (1H, m), 4.63 (2H, s), 6.48 (1H, s), 6.96 (1H, br s, D2O exch.), and 7.30 (15H, s).