Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]12([CH2:11][OH:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.CC(C)([O-])C.[K+].[Br:19][C:20]1[C:21](F)=[CH:22][C:23]([F:29])=[C:24]([CH:28]=1)[C:25]([OH:27])=[O:26].Cl.BrC1C(F)=CC=C(C=1)C(O)=O>CS(C)=O.O>[C:1]12([CH2:11][O:12][C:21]3[C:20]([Br:19])=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[C:23]([F:29])[CH:22]=3)[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: OCC12CC3CC(CC(C3)C1)C2
Reactant: O=C(O)c1cc(Br)c(F)cc1F
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: O=C(O)c1ccc(F)c(Br)c1
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)c1cc(Br)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Reaction time: 0.33 h

Procedure:
A mixture of adamantan-1-ylmethanol (3.51 g, 21.10 mmol) and potassium tert-butoxide (5.45 g, 48.5 mmol) in anhydrous dimethylsulfoxide (125 mL) was stirred for 20 minutes. To the reaction mixture was then added 5-bromo-2,4-difluorobenzoic acid (5.00 g, 21.10 mmol) followed by anhydrous dimethylsulfoxide (25 mL). The resulting mixture was stirred for 18 hours at ambient temperature. The reaction mixture was diluted with water (300 mL), and adjusted to pH 3 with 3 M hydrochloric acid. The obtained solid was filtered off and rinsed with water (200 mL) to provide a 2:1 mixture of the title compound and 2-adamantan-1-ylmethoxy)-5-bromo-4-fluorobenzoic acid (6.97 g, 86%). Major isomer: 1H NMR (300 MHz, DMSO-d6) δ 7.94 (d, J=7.9 Hz, 1H), 7.05 (d, J=12.9 Hz, 1H), 3.65 (s, 2H), 1.98-1.83 (m, 3H), 1.72-1.48 (m, 12H); MS (ES−) m/z 381.13, 383.12 (M−1).
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@H:21]([OH:23])[CH3:22])[CH2:12][C@@H:11]([O:31][Si](C(C)(C)C)(C)C)[CH2:10]1)(C(C)(C)C)(C)C.CC(C)([O-])C.[K+].C1OCCOC2C(=CC=CC=2)OCCOCCOC2C(=CC=CC=2)OC1.[O:71]1[C@@H:73]([CH:74]([CH3:76])[CH3:75])[CH2:72]1.[Si](O[C@@H]1[C@@]2(C)C(=CC=C3[C@@H]2CC[C@@]2(C)[C@H]3CC=C2[C@H](OC[C@@H](O)C(C)C)C)C[C@@H](O[Si](C(C)(C)C)(C)C)C1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C1(C)C=CC=CC=1>[OH:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@H:21]([O:23][CH2:72][C@@H:73]([OH:71])[CH:74]([CH3:76])[CH3:75])[CH3:22])[CH2:12][C@@H:11]([OH:31])[CH2:10]1
Reactant: C[C@@H](O)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(C)[C@H]1CO1
Agent: CC(C)(C)[O-]
Agent: CC(C)[C@H](O)CO[C@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)[C@H](O)CO[C@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Yield: 18.7 %

Procedure:
Using 1α,3β-bis(tert-butyldimethylsilyloxy)-20(R)-hydroxypregna-5,7,16-triene (79.0 mg, 0.141 mmol), potassium t-butoxide (190 mg, 1.69 mmol), dibenzo-18-crown-6 (25.0 mg, 0.0694 mmol), toluene (4.5 ml) and (S)-(+)-1,2-epoxy-3-methylbutane (0.15 ml, 1.43 mmol), alkylation reaction (108° C., 1 hour) and work up were performed by the same procedure as in Example 119, and then the residue was separated by preparative thin layer chromatography (0.5 mm×3, hexane:dichloromethane:ethyl acetate=45:5:2, developed three times) to give a fraction containing 1α,3β-bis(tert-butyldimethylsilyloxy)-20(R)-{2(S)-hydroxy-3-methylbutyloxy}pregna-5,7,16-triene (27.8 mg). This was deprotected with tetrahydrofuran (1 ml) and 1M tetra-n-butylammonium fluoride solution in tetrahydrofuran (0.25 ml) (reaction temperature 76° C., reaction period 13 hours) and worked up by the same procedure as in Example 119, and then the residue was purified by preparative thin layer chromatography (0.25 mm×1, dichloromethane:ethanol 15:1, developed twice) to give the title compound as a colorless oil (11.0 mg, 19%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([OH:6])=O.[O-:15][C:16]#[N:17].[K+].[OH-].[Na+].C(O)(C)C>C(O)(=O)C.O>[CH3:14][O:13][C:7]1[C:8]([O:11][CH3:12])=[CH:9][CH:10]=[C:2]2[C:3]=1[C:4](=[O:6])[NH:17][C:16](=[O:15])[NH:1]2
Reactant: COc1ccc(N)c(C(=O)O)c1OC
Reactant: N#C[O-]
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CC(C)O
Solvent: O
Product: COc1ccc2[nH]c(=O)[nH]c(=O)c2c1OC
Temperature: 60 °C
Reaction time: 2 h
Yield: 60.8 %

Procedure:
2-Amino-5,6-dimethoxybenzoic acid (10.5 g, 53.2 mM) was dissolved in glacial acetic acid (100 ml) and potassium cyanate (10.8 g, 133.0 mM) in 120 ml H2O was added gradually and stirred for 2 hours at 60° C. After cooling the reaction mixture to 20° C., sodium hydroxide pellets (78.2 g, 196 mole) were added while maintaining the temperature below 60° C. The reaction mixture was then heated at 90° C. for 45 minutes. Upon cooling in an ice bath, the sodium salt of the product precipitated, was filtered resuspended in H2O (120 ml), acidified (pH 3) with concentrated HCl, cooled, and filtered to give the crude product. Trituration with warm isopropanol afforded (60.8%) of a white solid, mp 266°-268° C.
Reaction SMILES: Cl.Cl.[C:3]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([N:16]3[CH:20]=[C:19]([CH3:21])[N:18]=[CH:17]3)=[CH:13][CH:14]=2)[C@H:9]([NH2:22])[CH2:8][C@@H:7]1[CH3:23])(=[O:5])[CH3:4].I[C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1.CC(C)([O-])C.[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(N(C)C)=CC=CC=2)CCCCC1>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:3]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([N:16]3[CH:20]=[C:19]([CH3:21])[N:18]=[CH:17]3)=[CH:13][CH:14]=2)[C@H:9]([NH:22][C:25]2[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=2)[CH2:8][C@@H:7]1[CH3:23])(=[O:5])[CH3:4]
Reactant: CC(=O)N1c2ccc(-n3cnc(C)c3)cc2[C@H](N)C[C@@H]1C
Reactant: COC(=O)c1ccc(I)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Product: COC(=O)c1ccc(N[C@@H]2C[C@H](C)N(C(C)=O)c3ccc(-n4cnc(C)c4)cc32)cc1
Temperature: 70 °C
Reaction time: 5 h
Yield: 13 %

Procedure:
A flask was charged with (cis)-1-acetyl-2-methyl-6-(4-methyl-1H-imidazol-1-yl)-1,2,3,4-tetrahydro-4-quinolinamine di-hydrochloride (for a preparation see Intermediate 61) (250 mg, 0.700 mmol), methyl 4-iodobenzoate (202 mg, 0.770 mmol), sodium tert-butoxide (235 mg, 2.449 mmol), 2′-(dicyclohexylphosphino)-N,N-dimethylbiphenyl-2-amine (DavePhos) (55.0 mg, 0.140 mmol) and tris(dibenzylideneacetone)dipalladium(0) (64.1 mg, 0.070 mmol) then filled with dried degassed toluene (15 mL) and the resulting mixture was stirred at 70° C. under nitrogen for 5 h then was cooled to room temperature and filtered through celite. The insoluble were rinsed with toluene (3×30 mL) and the combined filtrate and washings were concentrated in vacuo. The residue was partitioned between AcOEt (50 mL) and water (20 mL) and the layers were separated. The organic phase was washed with brine, and the combined aqueous phases were extracted with AcOEt (30 mL). The combined organic phases were dried over MgSO4 and concentrated in vacuo. Purification of the residue by SP4 using a 25 G silica cartridge (gradient:0 to 20% MeOH in DCM) gave methyl 4-{[(cis)-1-acetyl-2-methyl-6-(4-methyl-1H-imidazol-1-yl)-1,2,3,4-tetrahydro-4-quinolinyl]amino}benzoate (37 mg, 0.088 mmol, 13%).
Reaction SMILES: [CH2:1]([C:3]1[O:7][N:6]=[C:5]([C:8]2[S:12][C:11]([NH:13]C(=O)CC)=[N:10][C:9]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:4]=1)[CH3:2].Cl.C([O-])(O)=O.[Na+]>CO>[CH2:1]([C:3]1[O:7][N:6]=[C:5]([C:8]2[S:12][C:11]([NH2:13])=[N:10][C:9]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:4]=1)[CH3:2]
Reactant: CCC(=O)Nc1nc(-c2ccccc2)c(-c2noc(CC)n2)s1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CCc1nc(-c2sc(N)nc2-c2ccccc2)no1
Yield: 91 %

Procedure:
N-[5-(5-Ethyl-[1,2,4]oxadiazol-3-yl)-4-phenyl-thiazol-2-yl]-propionamide (1.02 g, 3.1 mmol) was suspended in MeOH (40 mL), konc. HCl(aq) was added and the reaction mixture was heated at refluc for 2 h. Saturated aqueous NaHCO3 (100 mL) was added to the reaction mixture. The aqueous phase was extracted with ethyl acetate (2×75 mL). The organic phase was dried with MgSO4 and the solvent was evaporated to yield white solid. Yield: 91%.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=3[OH:21])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[OH:22][C:23]1[C:28]([O:29][CH3:30])=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O>>[OH:22][C:23]1[C:28]([O:29][CH3:30])=[CH:27][CH:26]=[CH:25][C:24]=1[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=3[OH:21])[N:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: COc1cccc(B(O)O)c1O
Reactant: Cc1ccc(-c2cccc(-c3cccc(Br)n3)n2)c(O)c1
Product: COc1cccc(-c2cccc(-c3cccc(-c4ccc(C)cc4O)n3)n2)c1O
Yield: 33 %

Procedure:
6-(2-Hydroxy-3-methoxyphenyl)-6′-(2-hydroxy-4-methylphenyl)-2,2′-bipyridine was prepared from 6-bromo-6′-(2-hydroxy-4-methylphenyl)-2,2′-bipyridine and 2-hydroxy-3-methoxyphenylboronic acid in 33% yield using method F; δH [2H6]-DMSO 13.52,(2H, b), 8.31,(2H, dd), 8.26,(1H, d), 8.21,(1H, d), 8.12,(1H, d), 8.02,(1H, d), 7.70,(1H, d), 7.09,(1H, d), 6.92, (1H, t), 6.82,(1H, d), 3.86,(3H, s), 2.32,(3H, s); MS 385 (MH)+; HPLC retention time (system 1) 4.21 minutes.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:20][C:21]4[NH:27][C:26](=[O:28])[CH2:25][CH2:24][NH:23][C:22]=4[N:29]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:39]I.O>CN(C=O)C>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:19]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)=[CH:20][C:21]4[N:27]([CH3:39])[C:26](=[O:28])[CH2:25][CH2:24][NH:23][C:22]=4[N:29]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=O)CCN4)cc2)CCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1C(=O)CCNc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.3 %

Procedure:
To a solution of tert-butyl(1-(4-(2-oxo-8-phenyl-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazepin-7-yl)phenyl)cyclobutyl)carbamate (53 mg, 0.11 mmol) in dry DMF (1 ml) was added sodium hydride (4.4 mg, 0.11 mmol) and methyliodide (6.9 μl, 0.11 mmol) under nitrogen. The resulting mixture was stirred for 1 hour at room temperature. Water was added and the mixture was extracted with EtOAc (3×15 ml). The combined organic phases were dried over Na2SO4 and concentrated to dryness under reduced pressure. The resulting residue was purified by Biotage silica gel chromatography (gradient 0 to 57% EtOAc in cyclohexane) to give the title compound (21 mg, 38%). 1H NMR (500 MHz, CDCl3): 7.39 (1H, s), 7.27-7.23 (7H, m), 7.16-7.14 (2H, m), 5.04 (1H, s), 4.91 (1H, br s), 3.88 (2H, br s), 3.39 (3H, s), 2.74 (2H, t), 2.55-2.25 (4H, m), 2.10-2.03 (1H, m), 1.86-1.78 (1H, m), 1.44-1.15 (9H, br).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]([CH:7]=[CH:8][C:9](OC)=[O:10])=[CH:5][C:4]=1[O:15][CH2:16][C:17]1[N:18]=[C:19]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:20][C:21]=1[CH3:22].[H-].C([Al+]CC(C)C)C(C)C>>[CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6](/[CH:7]=[CH:8]/[CH2:9][OH:10])=[CH:5][C:4]=1[O:15][CH2:16][C:17]1[N:18]=[C:19]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:20][C:21]=1[CH3:22]
Reactant: COC(=O)C=Cc1ccc(OC)c(OCc2nc(-c3ccccc3)oc2C)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Product: COc1ccc(/C=C/CO)cc1OCc1nc(-c2ccccc2)oc1C

Procedure:
In substantially the same manner as in Reference Example 24, methyl 4-methoxy-3-(5-methyl-2-phenyl-4-oxazolylmethoxy)cinnamate was subjected to reduction with diisobutyl aluminum hydride to yield (E)-3-[4-methoxy-3-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]-2-propen-1-ol, which was recrystallized from ethyl acetate-ether to give pale yellow prisms, m.p.137-138° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([O:17][CH3:18])[CH:12]=3)=[CH:9][N:10]=2)[N:7]=1.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([NH2:32])[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([NH:32][C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([C:11]4[CH:16]=[CH:15][N:14]=[C:13]([O:17][CH3:18])[CH:12]=4)=[CH:9][N:10]=3)[N:7]=2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: COc1cc(-c2cnc3ccc(Cl)nn23)ccn1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Product: COc1cc(-c2cnc3ccc(NC4CCN(C(=O)OC(C)(C)C)CC4)nn23)ccn1
Yield: 59.8 %

Procedure:
292 mg of 4-[3-(2-methoxypyridin-4-yl)imidazo[1,2-b]pyridazin-6-ylamino]piperidine-1-carboxylic acid tert-butyl ester were prepared from 300 mg (1.15 mmol) of 6-chloro-3-(2-methoxypyridin-4-yl)imidazo[1,2-b]pyridazine (Example 1.14) and 230 mg (1.15 mmol) of 4-aminopiperidine-1-carboxylic acid tert-butyl ester (CAS No. 87120-72-7) by method A.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=2)=[O:10])=[N:6][CH:7]=1.[Br:21]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:21][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=2)=[O:10])=[N:6][CH:7]=1
Reactant: Cc1ccc(NC(=O)c2ccc3ccccc3c2)nc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(Nc1ccc(CBr)cn1)c1ccc2ccccc2c1
Yield: 38.7 %

Procedure:
N-(5-methylpyridin-2-yl)-2-naphthamide (1.31 g, 5.0 mmol), N-bromosuccinimide (0.89 g, 5.0 mmol) and benzoyl peroxide (0.12 g, 0.5 mmol) were dissolved in carbon tetrachloride (50 mL), and reacted under protection of nitrogen for 16 hours. It was filtered while hot, and the filter cake was washed with carbon tetrachloride. The filtrate was concentrated, chromatographed on a silica gel column (petroleum ether:ethyl acetate=5:1) to obtain a white solid 0.66 g, at a yield of 38.6%.
Reaction SMILES: [CH:1]1([C:4](=[O:24])[CH2:5][C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[C:10]([NH:18][CH3:19])[C:9]=2[S:20]([CH3:23])(=[O:22])=[O:21])=[O:7])[CH2:3][CH2:2]1.CO[CH:27](OC)[N:28]([CH3:30])[CH3:29]>CCCCCCC>[CH:1]1([C:4](=[O:24])[C:5](=[CH:27][N:28]([CH3:30])[CH3:29])[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:15])([F:17])[F:16])=[C:10]([NH:18][CH3:19])[C:9]=2[S:20]([CH3:23])(=[O:21])=[O:22])=[O:7])[CH2:3][CH2:2]1
Reactant: COC(OC)N(C)C
Reactant: CNc1c(C(F)(F)F)ccc(C(=O)CC(=O)C2CC2)c1S(C)(=O)=O
Solvent: CCCCCCC
Product: CNc1c(C(F)(F)F)ccc(C(=O)C(=CN(C)C)C(=O)C2CC2)c1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1.22 g (3.4 mmol) of 1-cyclopropyl-3-(3-methylamino-2-methylsulfonyl-4-trifluoromethylphenyl)propane-1,3-dione were treated with 3.0 ml (22.7 mmol) of N,N-dimethyl formamide dimethyl acetal and the mixture was stirred for 16 h at RT. Then, a little n-heptane was added, and the contents were stirred for a further 10 min at RT. The precipitate was filtered off with suction. This gave 1.29 g of product in 95% purity.
Reaction SMILES: [F:1][CH2:2][CH:3]([N:6]1[CH2:12][CH2:11][C:10]2[CH:13]=[C:14]([NH2:19])[C:15]([O:17][CH3:18])=[CH:16][C:9]=2[CH2:8][CH2:7]1)[CH2:4][F:5].Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[S:34]([CH:37]([CH3:39])[CH3:38])(=[O:36])=[O:35])[C:24]([Cl:40])=[CH:23][N:22]=1>>[Cl:40][C:24]1[C:25]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[S:34]([CH:37]([CH3:39])[CH3:38])(=[O:36])=[O:35])=[N:26][C:21]([NH:19][C:14]2[C:15]([O:17][CH3:18])=[CH:16][C:9]3[CH2:8][CH2:7][N:6]([CH:3]([CH2:2][F:1])[CH2:4][F:5])[CH2:12][CH2:11][C:10]=3[CH:13]=2)=[N:22][CH:23]=1
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: COc1cc2c(cc1N)CCN(C(CF)CF)CC2
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)C(C)C)n1)CCN(C(CF)CF)CC2

Procedure:
5-Chloro-N(2)-[3-(2-fluoro-1-fluoromethyl-ethyl)-8-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl]-N(4)-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine was prepared from 3-(2-fluoro-1-fluoromethyl-ethyl)-8-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and (2,5-dichloro-pyrimidin-4-yl)-[2-(propane-2-sulfonyl)-phenyl]-amine in an analogous manner to Example 308c. Product isolated as a white foam (95 mg 44%). LCMS (m/e) 580 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 9.52 (s, 1H), 8.57 (d, 1H, J=8.4 Hz), 8.17 (s, 1H), 8.00 (s, 1H), 7.94 (d, 1H, J=7.9 Hz), 7.67-7.58 (m, 1H), 7.50 (s, 1H), 7.32-7.24 (m, 1H), 6.67 (s, 1H), 4.76-4.66 (m, 2H), 4.65-4.55 (m, 2H), 3.89 (s, 3H), 3.33-3.10 (m, 2H), 2.91-2.79 (m, 6H), 2.79-2.69 (m, 2H), 1.35 (s, 3H), 1.33 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[CH2:12]([CH:14]([NH2:17])[CH2:15][CH3:16])[CH3:13].CCN(C(C)C)C(C)C>CCO>[Cl:1][C:2]1[N:7]=[C:6]([NH:17][CH:14]([CH2:15][CH3:16])[CH2:12][CH3:13])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: CCC(N)CC
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCC(CC)Nc1nc(Cl)ncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2,4-dichloro-5-nitro-pyrimidine (2 g, 10.31 mmol) in anhydrous EtOH (20 ml) is added 1-ethylpropylamine (1.322 ml, 11.341 mmol) at 0 C (ice bath) under inert atmosphere. To this is added neat DIPEA (2.694 ml, 15.465 mmol). The reaction is stirred at r.t. for 8 hrs. The reaction mixture was concentrated in vacuo and the residue is dissolved with EtOAc. The organic layer is washed with sat. NaHCO3 and brine, dried over Na2SO4, and concentrated in vacuo. Purification with column chromatography (SiO2, 1:3 EtOAC/Hexane) gives the desired product.
Reaction SMILES: S(O)(O)(=O)=O.[NH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[NH:12]1CC[CH2:15][CH2:14][CH2:13]1.S(=O)(=O)(O)O>CO>[N:6]1([CH:15]=[CH:14][C:13]#[N:12])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: C1CCNCC1
Agent: O=S(=O)(O)O
Solvent: CO
Product: N#CC=CN1CCCCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 59.2 %

Procedure:
30.3 g (0.25 mol) of sodium-3-hydroxyethylnitrile (content 75%) is added to a suspension of piperidine sulfate (prepared from 29.8 g (0.35 mol) of piperidine and 17.15 g (0.175 mol) of sulfuric acid) in 200 ml of methanol and stirred for 24 hours at 25° C. After working up as in Example 55, 28.2 g of 3-piperidinoacrylonitrile was obtained (82.9%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][C:7]([CH3:13])=[C:6]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:5]2=O.O.[NH2:22][NH2:23]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[C:6]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[C:7]([CH3:13])[NH:23][N:22]=2)[C:9]([OH:8])=[CH:10][C:11]=1[OH:12]
Reactant: NN
Reactant: Cc1oc2cc(O)c(Cl)cc2c(=O)c1-c1ccccc1
Solvent: O
Product: Cc1[nH]nc(-c2cc(Cl)c(O)cc2O)c1-c1ccccc1
Yield: 51.4 %

Procedure:
This compounds was synthesised in the same manner as described above. 6-Chloro-7-hydroxy-2-methyl-3-phenyl-chromen-4-one (0.5 g, 1.75 mmol), Hydrazine hydrate (5 ml). The quenched reaction was extracted into ethyl acetate, washed (water), dried (MgSO4), and the solvent removed under vacuum to give 4-Chloro-6-(5-methyl-4-phenyl-1H-pyrazol-3-yl)-benzene-1,3-diol as a white solid (0.27 g, 51.4%); Rf 0.55 ethyl acetate/hexane (80/20)].
Reaction SMILES: CO.[F:3][C:4]1[CH:5]=[C:6]([N+:16]([O-])=O)[CH:7]=[CH:8][C:9]=1[N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>[Ni].O>[F:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][C:9]=1[N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)[NH2:16]
Reactant: O=[N+]([O-])c1ccc(N2CCOCC2)c(F)c1
Agent: [Ni]
Solvent: CO
Solvent: O
Product: Nc1ccc(N2CCOCC2)c(F)c1
Temperature: 47.5 °C
Reaction time: 8 h
Yield: 90.3 %

Procedure:
Methanol (1.35 Lt) and 3-fluoro-4-morpholinyl nitrobenzene (134 gr) are added into autoclave and followed by Raney Nickel (20.5 gr). The system was flushed with nitrogen and hydrogen gas. The pressure of hydrogen was set to 4.0 kg/cm−2. The reaction mixture was stirred at 45-50° C. under H2 pressure for 8 hrs & the reaction followed by TLC until completion. The reaction mixture was filtered through celite and the filtrate is distilled off evaporate solvent completely U/vacuum at <50° C. temperature. Reaction mass is cooled to 25-30° C. To this DM water (400 ml) is added, Stirred for 1 hr at 25-30° C. The solid is filtered to give 105 gr of 3-fluoro-4-morpholinyl aniline.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=1[CH3:13].[Cl-].[Al+3].[Cl-].[Cl-]>Cl>[CH3:13][C:7]1[CH:8]=[C:9]([C:1]([CH3:2])=[O:3])[C:10]([F:12])=[CH:11][C:6]=1[Cl:5]
Reactant: CC(=O)Cl
Reactant: Cc1ccc(F)cc1Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CC(=O)c1cc(C)c(Cl)cc1F
Temperature: 120 °C
Reaction time: 2 h

Procedure:
At 60° C., 157 g of acetyl chloride were added dropwise to a mixture of 250 g of 2-chloro-4-fluorotoluene and 267 g of aluminum chloride. The reaction mixture was stirred at 120° C. for 2 hours and then, while still at 100° C., poured onto 2 l of an ice/water mixture. 180 ml of concentrated hydrochloric acid were subsequently stirred into the resulting mixture. The product was then extracted using three times 200 ml of dichloromethane. The organic phase was then washed with 200 ml of water, dried over sodium sulfate and finally concentrated. Yield: 290 g; oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[CH3:23][O:24][CH2:25][C:26]([C:29]1[CH:33]=[C:32]([NH:34][C:35](=O)[O:36]C2C=CC=CC=2)[O:31][N:30]=1)([CH3:28])[CH3:27].COC1C=C2C(=CC=1OC)N=CN=C2OC1C=C(NC(NC2ON=C(C(C)C)C=2)=O)C=CC=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([NH:19][C:35]([NH:34][C:32]2[O:31][N:30]=[C:29]([C:26]([CH3:28])([CH3:27])[CH2:25][O:24][CH3:23])[CH:33]=2)=[O:36])[CH:20]=[CH:21][CH:22]=1
Reactant: COCC(C)(C)c1cc(NC(=O)Oc2ccccc2)on1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Agent: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)C)no4)c3)c2cc1OC
Product: COCC(C)(C)c1cc(NC(=O)Nc2cccc(Oc3ncnc4cc(OC)c(OC)cc34)c2)on1
Yield: 54 %

Procedure:
3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113A (40 mg, 0.13 mmol) and phenyl 3-(1-methoxy-2-methylpropan-2-yl)isoxazol-5-ylcarbamate from the previous step (50 mg, 0.18 mmol) were reacted according to the method described for 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-isopropylisoxazol-5-yl)urea in Example 122B. Purification via preparative silica gel thin layer chromatography eluting with 10% methanol in dichloromethane afforded 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-(1-methoxy-2-methylpropan-2-yl)isoxazol-5-yl)urea as a pale yellow solid (35 mg, 54%). 1H NMR (300 MHz, DMSO-d6) δ 10.17 (brs, 1H), 9.05 (brs, 1H), 8.56 (s, 1H), 7.56 (s, 2H), 7.38-7.44 (m, 2H), 7.30 (m, 1H), 7.00 (m, 1H), 6.03 (s, 1H), 3.98-4.00 (2×s, 6H), 3.34 (s, 3H), 3.22 (s, 2H), 1.20 (s, 6H); LC-MS (ESI) m/z 494 (M+H)+.
Reaction SMILES: Br[C:2]1[C:11]2[O:10][CH2:9][CH2:8][N:7]([CH2:12][CH2:13][CH2:14][CH3:15])[C:6]=2[CH:5]=[C:4]([C:16]([O:18][CH3:19])=[O:17])[CH:3]=1.[Cu](C#N)[C:21]#[N:22].Cl>CN1C(=O)CCC1>[CH2:12]([N:7]1[C:6]2[CH:5]=[C:4]([C:16]([O:18][CH3:19])=[O:17])[CH:3]=[C:2]([C:21]#[N:22])[C:11]=2[O:10][CH2:9][CH2:8]1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCN1CCOc2c(Br)cc(C(=O)OC)cc21
Reactant: N#C[Cu]C#N
Agent: Cl
Solvent: CN1CCCC1=O
Product: CCCCN1CCOc2c(C#N)cc(C(=O)OC)cc21
Temperature: 175 °C
Reaction time: 8 h
Yield: 66.7 %

Procedure:
To a flask containing methyl 8-bromo-4-butyl-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate (0.33 g) was added NMP (7 mL), followed by copper cyanide (0.18 g). The mixture was then heated to 175° C. and stirred overnight. The resulting mixture was cooled to room temperature and poured into 1 N hydrochloric acid. The acidic aqueous layer was extracted with ethyl acetate, washed with 1 N hydrochloric acid (15 mL), saturated sodium bicarbonate (15 mL), and brine, dried (magnesium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 1:9 ethyl acetate/hexanes) provided 184 mg of the title compound: 1H NMR (300 MHz, CDCl3) δ 7.55, 7.43, 4.41, 3.89, 3.39, 3.31, 1.58, 1.40, 0.97.