Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@H:9]2[CH2:13][C@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20](Br)=[CH:19][C:18]=3[C:24]([F:27])([F:26])[F:25])(=[O:16])=[O:15])[CH2:11][C@@H:10]2[O:28][CH3:29])=[O:8])[CH2:5][CH2:4]1)#[N:2].[CH3:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.C(N(C(C)C)C(C)C)C.C([O-])([O-])=O.[Na+].[Na+]>CC(N(C)C)=O.O>[C:1]([C:3]1([NH:6][C:7]([C@H:9]2[CH2:13][C@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([N:34]4[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][CH2:33]4)=[CH:19][C:18]=3[C:24]([F:27])([F:26])[F:25])(=[O:16])=[O:15])[CH2:11][C@@H:10]2[O:28][CH3:29])=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: CO[C@H]1C[C@@H](S(=O)(=O)c2ccc(Br)cc2C(F)(F)F)C[C@@H]1C(=O)NC1(C#N)CC1
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Solvent: O
Product: CO[C@H]1C[C@@H](S(=O)(=O)c2ccc(N3CCN(C)CC3)cc2C(F)(F)F)C[C@@H]1C(=O)NC1(C#N)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 67.4 %

Procedure:
A mixture of (1R,2R,4R) and (1S,2S,4S)-4-(4-bromo-2-trifluoromethyl-benzenesulfonyl)-2-methoxy-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide (50 mg, 0.1009 mmol, example 58), 1-methylpiperazine (25 μl, 0.252 mmol) and N-ethyl-N,N-diisopropyl amine (36 μl, 0.202 mmol) in DMA (1 ml) was heated in a sealed tube to 100° C. for 5 h. Then additional 1-methylpiperazine (25 μl, 0.252 mmol) was added and heating to 100° C. was continued overnight. The mixture was then cooled to room temperature and diluted with water. The pH was adjusted to 10 by addition of saturated Na2CO3 solution and the mixture was extracted 3 times with EtOAc. The combined organic layers were washed two times with Na2CO3 solution (pH 10) and with brine, dried over Na2SO4 and evaporated. The remaining brown gum was purified by silica gel chromatography (DCM/MeOH 98:2-19:1) to obtain the title compound (35 mg, 67%) as white foam. MS (EI): 515.4 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:11][C:10]2[CH:9]=[N:8][C:7]([N:12](CO)[C:13]3[CH:18]=[C:17]([CH3:19])[C:16]([N:20]4[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]4)=[CH:15][C:14]=3[O:27][CH:28]([CH3:30])[CH3:29])=[N:6][C:5]=2[C:4]=1[C:33]1[C:34]([O:40][CH3:41])=[N:35][C:36]([CH3:39])=[CH:37][CH:38]=1.C(OC(C)C)(C)C.CCCCC>C1COCC1.[OH-].[Na+].C(OCC)(=O)C.O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(#N)C>[CH3:41][O:40][C:34]1[C:33]([C:4]2[C:5]3[N:6]=[C:7]([NH:12][C:13]4[CH:18]=[C:17]([CH3:19])[C:16]([N:20]5[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]5)=[CH:15][C:14]=4[O:27][CH:28]([CH3:29])[CH3:30])[N:8]=[CH:9][C:10]=3[S:11][C:3]=2[CH2:2][OH:1])=[CH:38][CH:37]=[C:36]([CH3:39])[N:35]=1
Reactant: COc1nc(C)ccc1-c1c(CO)sc2cnc(N(CO)c3cc(C)c(N4CCN(C)CC4)cc3OC(C)C)nc12
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCCCC
Solvent: CC(C)OC(C)C
Product: COc1nc(C)ccc1-c1c(CO)sc2cnc(Nc3cc(C)c(N4CCN(C)CC4)cc3OC(C)C)nc12
Yield: 40.9 %

Procedure:
A solution of 457 mg of the {[6-(hydroxymethyl)-7-(2-methoxy-6-methylpyridin-3-yl)thieno[3,2-d]pyrimidin-2-yl][5-methyl-4-(4-methylpiperazin-1-yl)-2-(propan-2-yloxy)phenyl]amino}methanol mixture in 30 ml of THF and 4.75 ml of 1 M sodium hydroxide is stirred at ambient temperature for 2 h 15. The mixture is diluted with 80 ml of ethyl acetate, 40 ml of water and 5 ml of an aqueous 10% citric acid solution. The aqueous phase is extracted three times with 40 ml of ethyl acetate. The organic phases are washed with 50 ml of a saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated under vacuum. The crude product is purified on 25 g of silica, elution being carried out with 1-5% of methanol (containing 10% by volume of 28% ammonium hydroxide) in dichloromethane, so as to obtain a brown oil. Placing the oil in solution in 1 ml of acetonitrile and adding diisopropyl ether and pentane gives a suspension which is concentrated under vacuum. After trituration with pentane, the resulting solid is filtered off and dried under vacuum, so as to obtain 177 mg of [7-(2-methoxy-6-methylpyridin-3-yl)-2-{[5-methyl-4-(4-methylpiperazin-1-yl)-2-(propan-2-yloxy)phenyl]amino}thieno[3,2-d]pyrimidin-6-yl]methanol in the form of a beige solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][NH:14][C:15]3[CH:16]=[C:17]([C:21](O)=[O:22])[N:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.[OH:25][CH2:26][CH:27]([NH2:29])[CH3:28]>>[OH:25][CH2:26][CH:27]([NH:29][C:21]([C:17]1[N:18]([CH3:20])[N:19]=[C:15]([NH:14][CH2:13][C:12]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[N:9][O:10][C:11]=2[CH3:24])[CH:16]=1)=[O:22])[CH3:28]
Reactant: CC(N)CO
Reactant: Cc1onc(-c2ccc(F)cc2)c1CNc1cc(C(=O)O)n(C)n1
Product: Cc1onc(-c2ccc(F)cc2)c1CNc1cc(C(=O)NC(C)CO)n(C)n1
Yield: 42 %

Procedure:
As described for example 144, 5-{[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-amino}-2-methyl-2H-pyrazole-3-carboxylic acid was converted, using 2-hydroxy-1-methylethylamine instead of 2-hydroxy-2-methylpropylamine, to the title compound (22 mg, 42%) which was obtained as a light yellow solid. MS: m/e=388.4 [M+H]+.
Reaction SMILES: [CH2:1]([OH:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13].N1C=CN=C1.[C:20]([Si:24](Cl)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([CH3:23])([CH3:22])[CH3:21]>CN(C=O)C>[Si:24]([O:14][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13])([C:20]([CH3:23])([CH3:22])[CH3:21])([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: OCCCCCCCCCCCCO
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OCCCCCCCCCCCCO)(c1ccccc1)c1ccccc1
Temperature: 45 °C
Reaction time: 48 h
Yield: 46 %

Procedure:
In a Schlenk flask, 1,12-Dodecandiol (7.96 g, 39.4 mmol, 1 eq) was dissolved in 40 mL of dry DMF under nitrogen. Imidazole (2.63 g, 38.6 mmol, 1 eq) and tert-butylchlorodiphenylsilane (TBDPS) (10.84 g, 39.4 mmol, 1 eq) were added and the reaction mixture was heated to 45° C. After stirring for 48 h, the reaction was quenched with 300 mL of distilled water. The aqueous phase was extracted four times with diethyl ether, the organic phases were collected and washed twice with 2N HCl (2×100 mL), once with saturated NaHCO3 (200 mL), once with saturated NaCl (200 mL) and dried over Na2SO4. Column-chromatography over silica gel using 10/1 hexane/ethyl acetate as eluent yielded 7.98 g (46%) of the desired product as a slightly yellowish oil. 1H NMR (300.13 MHz): δ (ppm)=1.05 (s, 9H, tert-butyl), 1.26 (br, 16H, —O—CH2—CH2—CH2—CH2—CH2—), 1.58 (m, 4H, —O—CH2—CH2—), 3.65 (m, 4H, —O—CH2—), 7.40 (m, 6H, phenyl), 7.69 (m, 4H, phenyl). 13C NMR (75.48 MHz): δ (ppm)=19.2, 25.7, 25.8, 25.9, 29.3, 29.4, 29.58, 29.6, 32.6, 32.8, 63.1, 64.0, 127.5, 129.4, 134.1, 135.6.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH2:13])=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.[O:14]=[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)=[CH:17][N:16]1[CH2:26][C:27](O)=[O:28].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C([O-])(O)=O.[Na+]>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:27](=[O:28])[CH2:26][N:16]3[CH:17]=[C:18]([C:21]4[S:22][CH:23]=[CH:24][CH:25]=4)[CH:19]=[CH:20][C:15]3=[O:14])=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: O=C(O)Cn1cc(-c2cccs2)ccc1=O
Reactant: COc1ccc2c(N)ccnc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc2c(NC(=O)Cn3cc(-c4cccs4)ccc3=O)ccnc2c1
Temperature: 40 °C
Yield: 40 %

Procedure:
To a solution of 7-methoxyquinolin-4-amine (0.13 g, 0.77 mmol) and 2-(2-oxo-5-(thiophen-2-yl)pyridin-1(2H)-yl)acetic acid (0.15 g, 0.64 mmol) in 5 mL of DMF at rt was added triethylamine (0.13 ml, 0.96 mmol) followed by HATU (0.44 g, 1.1 mmol) solid. The reaction was then heated up to 40° C. for 8 hours and was cooled to rt and diluted with 60 mL of EtOAc and 30 mL of satd. NaHCO3 (aq.) solution. The organic phase was separated, washed with 30 mL of brine and dried over Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (EtOAc to 10% MeOH/EtOAc) to give white (0.10 g, 40% yield). MS (ESI pos. ion) m/z (MH+): 392.1. Calc'd Exact Mass for C21H17N3O3S: 391.1.
Reaction SMILES: O[CH2:2][C:3]1[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=1[CH:5]([C:8]1[S:12][CH2:11][N:10]([CH3:13])[CH:9]=1)[O:6][CH3:7].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:38]>C(#N)C>[Cl:38][CH2:2][C:3]1[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=1[CH:5]([C:8]1[S:12][CH2:11][N:10]([CH3:13])[CH:9]=1)[O:6][CH3:7]
Reactant: COC(C1=CN(C)CS1)c1ccccc1CO
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: COC(C1=CN(C)CS1)c1ccccc1CCl
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
To a mixture of 1.24 g (5.3 mmol) of 5-(2-hydroxymethyl-α-methoxybenzyl)-3-methylthiazole and 10 ml of acetonitrile was added 1.67 g (6.36 mmol) of triphenylphosphine and 1.23 ml (12.7 mmol) of carbon tetrachloride under ice-cooling and stirred at room temperature overnight. After completion of the reaction, the residue obtained by concentration under reduced pressure was purified by column chromatography on silica gel (ethyl acetate/n-hexane) to give 5-(2-chloromethyl-α-methoxybenzyl)-3-methylthiazole (1.03 g, 77.2%) as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[C:11]([O:15][CH2:16][CH3:17])(=[O:14])[CH:12]=[CH2:13].C(=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+]>CN(C)C=O>[Cl:1][C:2]1[C:3]2[N:10]([CH2:13][CH2:12][C:11]([O:15][CH2:16][CH3:17])=[O:14])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: C=CC(=O)OCC
Reactant: Clc1ncnc2cc[nH]c12
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCn1ccc2ncnc(Cl)c21
Temperature: 25 °C
Reaction time: 7.5 h

Procedure:
4-Chloro-5H-pyrrolo[3,2-d]pyrimidine (303 mg) was dissolved in N,N-dimethylformamide (9 mL), ethyl acrylate (0.3 mL) and potassium carbonate (538 mg) were sequentially added, and the mixture was stirred at room temperature for 7.5 hrs. Ethyl acrylate (0.2 mL) was added, and the mixture was stirred for 16 hrs. Ethyl acrylate (0.3 mL) and potassium carbonate (526 mg) were further added, and the mixture was stirred for 6 hrs. The reaction mixture was treated with saturated aqueous ammonium chloride solution and the mixture was extracted with ethyl acetate. The organic layer washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=66:34→20:80) to give the title compound (404 mg) as a colorless oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1.O[C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][CH:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH:23]([C:22]1[CH:25]=[CH:26][C:19]([O:1][CH2:2][CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]2)=[CH:20][CH:21]=1)=[O:24]
Reactant: O=Cc1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(CCCO)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(CCCOc2ccc(C=O)cc2)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 81.2 %

Procedure:
To 0.5 g (2.05 mmol) of tert-butyl 4-(3-hydroxypropyl)piperazine-1-carboxylate, 0.3 g (2.46 mmol) of 4-hydroxybenzaldehyde and 1 g (3.07 mmol) of resin-supported triphenyl-phosphine (3 mmol/g of resin) diluted in 14.5 ml of anhydrous tetrahydrofuran, is added dropwise at 0° C. under argon 0.614 ml (3.07 mmol) of diisopropyldiazene-1,2-dicarboxylate. The reaction mixture is stirred at room temperature for 20 h. The solid is filtered then rinsed in dichloromethane. The filtrate is concentrated and diluted in a sodium hydroxide solution (1M) and the product is extracted several times with ethyl acetate. The organic phases are combined, dried over magnesium sulfate, and concentrated. The residue is purified by chromatography on silica (cyclohexane/ethyl acetate eluent: 4:6 to 100% ethyl acetate) to yield 0.58 g of tert-butyl 4-(3-(4-formylphenoxy)propyl)piperazine-1-carboxylate in the form of a colourless oil.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6]([C:10]([F:13])([F:12])[F:11])=[CH:5][N:4]=1.[CH2:14]([S:16][C:17]1[N:21]([CH3:22])[N:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[C:18]=1[CH:27]=O)[CH3:15].S([O-])([O-])=O.[Na+].[Na+].C(=O)(O)[O-].[Na+]>[Cu](Cl)Cl.C(OCC)(=O)C.CN(C)C(=O)C>[CH2:14]([S:16][C:17]1[N:21]([CH3:22])[N:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[C:18]=1[C:27]1[N:2]([CH3:1])[C:3]2=[N:4][CH:5]=[C:6]([C:10]([F:11])([F:12])[F:13])[CH:7]=[C:8]2[N:9]=1)[CH3:15]
Reactant: CNc1ncc(C(F)(F)F)cc1N
Reactant: CCSc1c(C=O)c(C(F)(F)F)nn1C
Agent: Cl[Cu]Cl
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CCSc1c(-c2nc3cc(C(F)(F)F)cnc3n2C)c(C(F)(F)F)nn1C
Temperature: 150 °C
Reaction time: 8 h
Yield: 76.1 %

Procedure:
A mixture of 0.22 g of N2-methyl-5-trifluoromethylpyridine-2,3-diamine, 0.26 g of 5-ethylthio-1-methyl-3-trifluoromethyl-1H-pyrazole-4-carboaldehyde, 0.18 g of sodium sulfite, 0.31 g of copper(II) chloride (anhydrous) and 2 ml of N,N-dimethylacetamide was stirred at 150° C. for 8 hours. Ethyl acetate and a saturated aqueous sodium bicarbonate solution were poured into the cooled reaction mixture, and the mixture was filtered. The aqueous layer of the filtrate was extracted with ethyl acetate and then combined with the organic layer of the filtrate, and the mixture was washed with water and dried over anhydrous magnesium sulfate. The mixture was concentrated under reduced pressure, then the resulting residue was applied to a silica gel column chromatography to obtain 0.34 g of 2-(5-ethylthio-1-methyl-3-trifluoromethyl-1H-pyrazol-4-yl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (Compound of Present Invention (25)).
Reaction SMILES: CC(C)([O-])C.[Na+].[CH2:7]([NH2:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:62]1[CH:63]=[C:64]([CH:69]([O:80][CH3:81])[C:70]2([C:73]([O:75][C:76]([CH3:79])([CH3:78])[CH3:77])=[O:74])[CH2:72][CH2:71]2)[CH:65]=[CH:66][C:67]=1[Cl:68].[Cl-].[NH4+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH2:7]([NH:14][C:66]1[CH:65]=[C:64]([CH:69]([O:80][CH3:81])[C:70]2([C:73]([O:75][C:76]([CH3:77])([CH3:78])[CH3:79])=[O:74])[CH2:71][CH2:72]2)[CH:63]=[CH:62][C:67]=1[Cl:68])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COC(c1ccc(Cl)c(Br)c1)C1(C(=O)OC(C)(C)C)CC1
Reactant: NCc1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(c1ccc(Cl)c(NCc2ccccc2)c1)C1(C(=O)OC(C)(C)C)CC1
Temperature: 110 °C

Procedure:
In a dry reaction flask which had been flushed with argon, 4.60 g (47.9 mmol) of sodium tert-butoxide were suspended in 100 ml of abs. toluene, and 5.2 ml (47.9 mmol) of benzylamine, 0.99 g (1.6 mmol) of rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, 1.83 g (2.0 mmol) of tris(dibenzylideneacetone)dipalladium and 15.0 g (39.9 mmol) of (+/−)-tert-butyl 1-[(3-bromo-4-chlorophenyl)(methoxy)methyl]cyclopropanecarboxylate were added. The reaction mixture was heated at 110° C. for 3 h. After cooling, ethyl acetate and saturated aqueous ammonium chloride solution were added and the mixture was filtered through Celite. The organic phase was washed with saturated ammonium chloride solution and saturated sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 40:1→20:1). This gave 12.0 g of the target compound (74.8% of theory).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][OH:12])=[CH:8][CH:9]=2)[N:4]=[CH:3][CH:2]=1>[O-2].[Mn+4].[O-2].ClCCl>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[O:12])=[CH:8][CH:9]=2)[N:4]=[CH:3][CH:2]=1
Reactant: OCc1ccc2nccnc2c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=Cc1ccc2nccnc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.3 %

Procedure:
To a stirred solution of 10 parts of intermediate 5, namely 6-quinoxalinemethanol in 133 parts of dichloromethane were added 20 parts of manganese(IV) oxide. After stirring for 3 hours at room temperature, the reaction mixture was filtered and the filtrate was evaporated, yielding 6.6 parts (67.3%) of 6-quinoxalinecarboxaldehyde; mp. 134° C. (interm. 6).
Reaction SMILES: [F:1][CH:2]([F:12])[C:3]1[CH:4]=[C:5]([C:9](=O)[CH3:10])[CH:6]=[CH:7][CH:8]=1.[CH3:13][C:14]([S@:17]([NH2:19])=[O:18])([CH3:16])[CH3:15]>>[F:1][CH:2]([F:12])[C:3]1[CH:4]=[C:5]([CH:9]([NH:19][S@@:17]([C:14]([CH3:16])([CH3:15])[CH3:13])=[O:18])[CH3:10])[CH:6]=[CH:7][CH:8]=1
Reactant: CC(=O)c1cccc(C(F)F)c1
Reactant: CC(C)(C)[S@](N)=O
Product: CC(N[S@](=O)C(C)(C)C)c1cccc(C(F)F)c1
Yield: 56 %

Procedure:
The title compound is prepared in 56% yield (0.53 g, colorless oil) from 1-(3-(difluoromethyl)phenyl)ethanone (0.58 g, 3.41 mmol, Step-1) and (R)-2-methylpropane-2-sulfinamide by the similar manner in Step-4 of Amine-1.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)[C:4]#[N:5].C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>O1CCCC1>[CH3:18][S:19]([O:1][N:2]=[C:3]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)[C:4]#[N:5])(=[O:21])=[O:20]
Reactant: N#CC(=NO)c1cccs1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)ON=C(C#N)c1cccs1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
In general analogy to the reaction described under 3.2, 38 g (0.25 mol) of α-hydroxyiminothiophene-2-acetonitrile and 37.95 g (0.375 mol) of triethylamine are dissolved in 350 ml of tetrahydrofuran and to this solution is then added dropwise a solution of 31.5 g (0.275 mol) of methanesulfonyl chloride at 0-5° C. After the addition is complete, the mixture is stirred for 30 minutes at 0° C. and then overnight at room temperature. The reaction mixture is filtered, the filtrate is washed with saturated sodium chloride solution and dried over magnesium sulfate. The solvent is distilled off on a rotary evaporator, giving a grey solid which is then recrystallised from toluene. 52.4 g (91%) of α-(methylsulfonyloxyimino)thiophene-2-acetonitrile are obtained in the form of beige crystals having an m.p. of 108-111° C. The 1H-NMR spectrum shows it to be a 55:45 mixture of the cis- and trans-isomers.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:17])=[CH:4][C:5]2[C:6]([CH3:16])([CH3:15])[CH2:7][CH:8]=[C:9]([CH:12]([CH3:14])[CH3:13])[C:10]=2[CH:11]=1.[C:18]([C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:29]=1)[CH2:25]Br)([CH3:21])([CH3:20])[CH3:19]>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5](=[CH:4][C:3]=1[O:17][CH2:25][C:24]1[CH:23]=[C:22]([C:18]([CH3:20])([CH3:19])[CH3:21])[CH:29]=[C:28]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:27]=1)[C:6]([CH3:15])([CH3:16])[CH2:7][CH:8]=[C:9]2[CH:12]([CH3:13])[CH3:14]
Reactant: CC(C)C1=CCC(C)(C)c2cc(O)c(Br)cc21
Reactant: CC(C)(C)c1cc(CBr)cc(C(C)(C)C)c1
Product: CC(C)C1=CCC(C)(C)c2cc(OCc3cc(C(C)(C)C)cc(C(C)(C)C)c3)c(Br)cc21
Yield: 72 %

Procedure:
Following General Procedure O, 3-bromo-5-isopropyl-8,8-dimethyl-7,8-dihydronaphthalen-2-ol (Compound 97, 0.14 g, 0.48 mmol) was reacted with 3,5-di-t-butylbenzylbromide to afford 0.074 g (72%) of the title compound as a yellow solid. PNMR (300 MHz, CDCl3) δ 1.20 (m, 12 H), 1.37 (s, 18 H), 2.15 (d, 2 H, J=4.8 Hz), 2.85 (m, 1 H), 5.20 (s, 2 H), 5.72 (m, 3 H), 6.95 (s, 1 H), 7.40 (m, 3 H), 7.55 (s, 1 H).
Reaction SMILES: C([Li])(CC)C.CN(C)[CH:8]=[O:9].[CH:11]1([O:16][C:17]2[CH:18]=[C:19]([CH:27]=[CH:28][C:29]=2[O:30][CH3:31])[C:20]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[O:21])[CH2:15][CH2:14][CH2:13][CH2:12]1.NCCCCN.P([O-])([O-])([O-])=O.Cl>O1CCCC1.C(OCC)(=O)C>[CH:11]1([O:16][C:17]2[C:18]([CH:8]=[O:9])=[C:19]([CH:27]=[CH:28][C:29]=2[O:30][CH3:31])[C:20]([N:22]([CH2:23][CH3:24])[CH2:25][CH3:26])=[O:21])[CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: CCN(CC)C(=O)c1ccc(OC)c(OC2CCCC2)c1
Reactant: CN(C)C=O
Agent: Cl
Agent: NCCCCN
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCN(CC)C(=O)c1ccc(OC)c(OC2CCCC2)c1C=O
Temperature: -75 °C
Yield: 34.7 %

Procedure:
At −75° C. under stirring, sec-butyl-lithium (195.76 ml, 0.231 moles) and, after 1 hour, at the same temperature, dimethylformamide (53.66 ml, 0.693 moles) were added dropwise to a solution of 3-cyclopentyloxy-N,N-diethyl-4-methoxy-benzamide (61.2 g, 0.21 moles), obtained as described in example 3, and of tetramethylendiamine (34.86 ml, 0.231 moles) in anhydrous tetrahydrofuran (480 ml). After further half an hour at −75° C., the reaction mixture was poured into a pH=7 phosphate buffer, ethyl acetate and concentrated HCl. The extraction was repeated further twice with fresh ethyl acetate, then the extract was washed with 5% potassium bisulphate, then with water, then dried on sodium sulphate and evaporated to dryness. The residue was cromatographed on silica gel (eluent petrolatum/ethyl acetate 1:1) to give 23.3 g of the title compound (yield: 35%).
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][C:9]([OH:11])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:54][C:55]1[CH:56]=[C:57]([C:61]2[N:70]=[C:69]([NH:71][C:72]3[CH:73]=[C:74]4[C:78](=[CH:79][CH:80]=3)[N:77]([C:81]([O:83][C:84]([CH3:87])([CH3:86])[CH3:85])=[O:82])[N:76]=[CH:75]4)[C:68]3[C:63](=[CH:64][CH:65]=[CH:66][CH:67]=3)[N:62]=2)[CH:58]=[CH:59][CH:60]=1>C(Cl)Cl>[C:1]([O:5][C:6]([CH2:8][C:9]([NH:54][C:55]1[CH:56]=[C:57]([C:61]2[N:70]=[C:69]([NH:71][C:72]3[CH:73]=[C:74]4[C:78](=[CH:79][CH:80]=3)[N:77]([C:81]([O:83][C:84]([CH3:87])([CH3:86])[CH3:85])=[O:82])[N:76]=[CH:75]4)[C:68]3[C:63](=[CH:64][CH:65]=[CH:66][CH:67]=3)[N:62]=2)[CH:58]=[CH:59][CH:60]=1)=[O:11])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(N)c4)nc4ccccc34)ccc21
Reactant: CC(C)(C)OC(=O)CC(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CC(=O)Nc1cccc(-c2nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c3ccccc3n2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A suspension of 2-(tert-butoxycarbonyl)acetic acid (21 mg, 0.11 mmol), PyBOP® (57 mg, 0.11 mmol), DIEA (38 μL, 0.22 mmol) in anhydrous CH2Cl2 (0.5 mL) was stirred at RT for 10 minutes. This solution of activated acid was added to a suspension of tert-butyl 5-(2-(3-aminophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (100 mg, 0.22 mmol) and anhydrous CH2Cl2 (1 mL). The reaction mixture was stirred at RT for 1 h. Activated and added another 0.5 equivalent of the acid as described above and stirred for 1 h. Activated and added another 0.3 equivalents of the acid as described above. Stirred for and additional hour and diluted with CH2Cl2. Extracted with H2O (3×) and the organic layer was dried under Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography on silica (1:1 EtOAc:Hexanes) to give the desired product tert-butyl 5-(2-(3-(2-(tert-butoxycarbonyl)acetamido)phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate. (123 mg, 0.20 mmol, 90%).