Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](Br)[N:3]=1.[CH:9]1(B(O)O)[CH2:11][CH2:10]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>O.C(OCC)(=O)C.CC([O-])=O.CC([O-])=O.[Pd+2].C1(C)C=CC=CC=1>[CH:9]1([C:4]2[N:3]=[C:2]([NH2:1])[CH:7]=[CH:6][CH:5]=2)[CH2:11][CH2:10]1
Reactant: Nc1cccc(Br)n1
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Nc1cccc(C2CC2)n1
Temperature: 100 °C
Yield: 36.3 %

Procedure:
To a sealable vial under nitrogen was added 2-amino-6-bromo-pyridine (1.6 g), cyclopropyl boronic acid (1.03 g) (prepared according to Wallace et al. Tetrahedron Lett. 2002, 43, 6987-6990), potassium phosphate (6.87 g), tricyclohexylphosphine (0.260 g) followed by water (2 mL) and toluene (40 mL). Pd(OAc)2 (0.104 g) was then added and the vial was sealed and heated at 100° C. over 16 hours. The reaction was then allowed to cool to ambient temperature and diluted with water and ethyl acetate. The phases were separated and the aqueous phase was extracted with more ethyl acetate (3×). The combined phases were washed with brine and dried over sodium sulfate. Filtration and evaporation of the volatiles afforded a crude residue which was purified via ISCO Combiflash chromatography using ethyl acetate/heptane as the eluent to give the desired 6-cyclopropyl-pyridin-2-ylamine as yellow solid (0.450 g).
Reaction SMILES: C(N1CCN(C2SC(C(O)=O)=C(C)N=2)C1=O)C1C=CC=CC=1.[F:23][CH:24]([F:48])[O:25][C:26]1[CH:47]=[CH:46][C:29]([CH2:30][N:31]2[CH2:35][CH2:34][N:33]([C:36]3[S:37][C:38]([C:42]([OH:44])=O)=[C:39]([CH3:41])[N:40]=3)[C:32]2=[O:45])=[CH:28][CH:27]=1.[NH2:49][CH2:50][C:51]1[CH:52]=[N:53][CH:54]=[CH:55][CH:56]=1>>[F:48][CH:24]([F:23])[O:25][C:26]1[CH:27]=[CH:28][C:29]([CH2:30][N:31]2[CH2:35][CH2:34][N:33]([C:36]3[S:37][C:38]([C:42]([NH:49][CH2:50][C:51]4[CH:52]=[N:53][CH:54]=[CH:55][CH:56]=4)=[O:44])=[C:39]([CH3:41])[N:40]=3)[C:32]2=[O:45])=[CH:46][CH:47]=1
Reactant: Cc1nc(N2CCN(Cc3ccc(OC(F)F)cc3)C2=O)sc1C(=O)O
Reactant: NCc1cccnc1
Agent: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)O
Product: Cc1nc(N2CCN(Cc3ccc(OC(F)F)cc3)C2=O)sc1C(=O)NCc1cccnc1
Yield: 65 %

Procedure:
Following the procedure as describe in Example 9, making variations as required to replace 2-(3-benzyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 2-(3-(4-(difluoromethoxy)benzyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid to react with 3-(aminomethyl)pyridine in place of benzylamine, the title compound was obtained as a white powder in 65% yield: mp 166-167° C.; 1H NMR (300 MHz, CDCl3) δ 8.55-8.40 (m, 3H), 7.67 (d, J=7.8 Hz, 1H), 7.43-6.94 (m, 6H), 4.45-4.35 (m, 4H), 3.97 (t, J=8.1 Hz, 2H), 3.39 (t, J=8.1 Hz, 2H), 2.46 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 162.3, 157.8, 155.5, 151.7, 150.7, 149.3, 148.4, 135.6, 133.8, 130.0, 123.9, 120.1, 119.4, 117.9, 115.0, 46.6, 42.4, 42.0, 40.8, 17.5; MS (ES+) m/z 474.3 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][C:4]=1[C:10]1[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH:15]=1.[Br:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>>[Br:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([C:10]3[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH:11]=3)[CH:5]=2)(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: COc1ccc(N)cc1C1=CCN(C)CC1
Product: COc1ccc(NS(=O)(=O)c2ccc(Br)cc2)cc1C1=CCN(C)CC1

Procedure:
The title compound (E129) was prepared from 4-methoxy-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)phenylamine (free base of D39) (107 mg; 0.49 mmol) and 4-bromobenzenesulfonylchloride (125 mg, 0.49 mmol) using the method of Example 1 (179 mg, 77%) MH+=437/439.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[O:10]([CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].CC(C)([O-])C.[Na+].C(OCC)(=O)C>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:10]([CH:18]1[CH2:23][CH2:22][N:21]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[CH2:20][CH2:19]1)[Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: CC(C)(C)[Si](C)(C)OC1CCNCC1
Reactant: N#Cc1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OC1CCN(c2ccc(C#N)cc2)CC1
Temperature: 80 °C
Reaction time: 1 h
Yield: 64.2 %

Procedure:
A mixture of 4-bromobenzonitrile (2.76 g, 15.16 mmol), 4-(tert-butyldimethylsiloxy)piperidine (2.9 g, 13.79 mmol), palladium acetate (62 mg, 0.28 mmol), (S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP) (258 mg, 0.41 mmol), and sodium tert-butoxide (1.99 g, 20.68 mmol) in toluene (60 ml) was stirred at 80° C. for 1 hour. The reaction mixture was allowed to return to room temperature, to which ethyl acetate (60 ml) was added, and the mixture was filtered. The filtration was washed with water and brine, and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/methylene chloride=1/1) to afford 4-[4-(tert-butyldimethylsiloxy)piperidin-1-yl]benzonitrile (2.8 g, yield 66%) as a pale yellow crystalline powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:55])[C@@H:4]([NH:20][C:21]([C@@H:23]1[CH2:36][C:35]2[CH:34]=[C:33]3[C:28]([O:29][C@@H:30]([C:39]4[CH:44]=[CH:43][C:42]([OH:45])=[CH:41][CH:40]=4)[C:31](=[O:38])[N:32]3[CH3:37])=[CH:27][C:26]=2[CH2:25][N:24]1[C@@H:46]([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[CH2:47][CH3:48])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[Cl:56][C:57]1[CH:58]=[C:59]([CH:62]=[CH:63][C:64]=1[Cl:65])[CH2:60]Br.C(=O)([O-])[O-].[K+].[K+].C(=O)(O)[O-].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:55])[C@@H:4]([NH:20][C:21]([C@@H:23]1[CH2:36][C:35]2[CH:34]=[C:33]3[C:28]([O:29][C@@H:30]([C:39]4[CH:40]=[CH:41][C:42]([O:45][CH2:60][C:59]5[CH:62]=[CH:63][C:64]([Cl:65])=[C:57]([Cl:56])[CH:58]=5)=[CH:43][CH:44]=4)[C:31](=[O:38])[N:32]3[CH3:37])=[CH:27][C:26]=2[CH2:25][N:24]1[C@@H:46]([C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1)[CH2:47][CH3:48])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][CH:17]=2)=[CH:8][CH:7]=1
Reactant: Clc1ccc(CBr)cc1Cl
Reactant: CC[C@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)N[C@@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)C(=O)OC)N(C)C(=O)[C@H](c1ccc(O)cc1)O3
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC[C@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)N[C@@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)C(=O)OC)N(C)C(=O)[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Temperature: 25 °C
Reaction time: 6 h

Procedure:
(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(3S,7S)-3-(4-hydroxy-phenyl)-1-methyl-2-oxo-6-((R)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid methyl ester (0.177 mmol) was dissolved in 2 mL of DMF and 3,4-dichlorobenzyl bromide (0.885 mmol) and potassium carbonate (0.885 mmol) were added. The mixture was stirred at room temperature for 6 hours and was poured onto ethyl acetate and saturated sodium bicarbonate. The organic layer was dried over sodium sulfate and concentrated. The residue was purified over silica (hexanes-ethyl acetate-MeOH, 7-3-0.1) to provide (S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(3S,7S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((R)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid methyl ester. 1H NMR (400 MHz, d6 acetone): 7.77-7.86 (m, 5H), 7.60 (d, 1H), 7.54 (m, 3H), 7.37 (dd, 1H), 7.32-7.18 (m, 7H), 6.97 (d, 1H), 6.92 (s, 1H), 6.82 (m, 3H), 6.78 (m, 2H), 6.71 (s, 1H), 5.65 (s, 1H), 4.95 (m, 2H), 4.66 (m, 1H), 3.76 (m, 2H), 3.70 (s, 3H), 3.58 (m, 2H), 3.40 (s, 3H), 3.06 (m, 2H), 3.02 (m, 2H), 2.83-2.72 (m, 2H), 1.96-1.7 (m, 2H), 0.54 (t, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[C:15]([F:21])[CH:14]=3)[C:11]([CH3:23])(O)[O:10][N:9]=2)=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[C:15]([F:21])[CH:14]=3)=[C:11]([CH3:23])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: CSc1ccc(C2C(c3ccc(Br)cc3)=NOC2(C)O)cc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: CSc1ccc(-c2c(-c3ccc(Br)cc3)noc2C)cc1F
Yield: 96.9 %

Procedure:
A mixture of 3-(4-bromophenyl)-4-(3-fluoro-4-methylthiophenyl)-5-methyl-4,5-dihydro-5-isoxazolol (630 mg, 1.59 mmol) and p-toluenesulfonic acid monohydrate (274 mg, 1.59 mmol) in methanol (10 ml) was refluxed for 2 h. The mixture was evaporated, dissolved in ethyl acetate (100 ml), washed with saturated sodium bicarbonate (50 ml×2), and dried over anhydrous sodium sulfate. Removal of solvent gave 583 mg (97%) of the title compound as a pale yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([OH:18])[CH2:9][CH2:10][NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH:5]=[CH:6][CH:7]=1.[CH3:19][CH:20]([CH3:24])[CH2:21][C:22]#[CH:23]>>[F:14][C:13]([F:16])([F:15])[C:12]([NH:11][CH2:10][CH2:9][CH:8]([OH:18])[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:23]#[C:22][CH2:21][CH:20]([CH3:24])[CH3:19])[CH:3]=1)=[O:17]
Reactant: C#CCC(C)C
Reactant: O=C(NCCC(O)c1cccc(Br)c1)C(F)(F)F
Product: CC(C)CC#Cc1cccc(C(O)CCNC(=O)C(F)(F)F)c1

Procedure:
Sonogashira reaction of 25 with 4-methyl-pent-1-yne yielded 2,2,2-trifluoro-N-(3-hydroxy-3-(3-(4-methylpent-1-ynyl)phenyl)propyl)acetamide as dark brown oil. Yield (0.94 g, 94%): 1H NMR (400 MHz, CDCl3) δ 7.38 (s, 1H), 7.25-7.35 (m, 3H), 4.86 (m, 1H), 3.67-3.72 (m, 1H), 3.38-3.44 (m, 1H), 2.30 (d, J=6.4 Hz, 2H), 2.28 (bs, 1H), 1.87-1.99 (m, 3H), 1.05 (d, J=6.8 Hz, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6].[CH3:14][S:15](Cl)(=[O:17])=[O:16]>N1C=CC=CC=1>[CH3:13][O:12][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[NH:1][S:15]([CH3:14])(=[O:17])=[O:16]
Reactant: COC(=O)c1ccc(OC)c(N)c1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(OC)c(NS(C)(=O)=O)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 91 %

Procedure:
A solution of methyl 3-amino-4-methoxybenzoate (prepared in an analogous manner to that described in Scheme 17, Step 1) (2.00 g, 11.04 mmol) in dry pyridine (25 ml) was cooled to 0° C.; methanesulfonyl chloride (1.115 ml, 14.35 mmol) was added drop wise, and the mixture was warmed to RT and stirred for 3 hours. The solvent was evaporated under vacuum, and the residue was partitioned between DCM and HCl 2N. The organic layer was washed with brine and dried over Na2SO4; the solvent was removed; and the residue was triturated with iPr2O to give methyl 4-methoxy-3-(methylsulfonamido)benzoate (2.6 g, 10.03 mmol, 91% yield, MS/ESI+ 260.1 [MH]+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[CH:12][C:11]([C:20]#[N:21])=[C:10](O)[N:9]=2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:25].N>CN(C=O)C>[Cl:25][C:10]1[N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:13]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:12][C:11]=1[C:20]#[N:21]
Reactant: N#Cc1cc(-c2ccncc2)c(-c2ccc(F)cc2)nc1O
Reactant: O=P(Cl)(Cl)Cl
Agent: N
Solvent: CN(C)C=O
Product: N#Cc1cc(-c2ccncc2)c(-c2ccc(F)cc2)nc1Cl
Yield: 55.4 %

Procedure:
A mixture of 2-(4-fluorophenyl)-6-hydroxy-3,4′-bipyridine-5-carbonitrile (6.57 g, 22.5 mmol, obtained in reference example 10), POCl3 (26.3 mL, 287.5 mmol) and DMF (0.37 mL) was heated to reflux under argon atmosphere for 2 h. It was cooled with an ice bath and basified by adding 30% aqueous NH3. The precipitate obtained was filtered and washed with water. The product was purified by chromatography on silica gel using hexane-EtOAc mixtures of increasing polarity as eluent, to afford 3.86 g of the desired product as a yellow solid (yield: 55%).
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:7]=[CH:8][C:9]3[C:10]4[S:30][CH:29]=[CH:28][C:11]=4[C:12]([NH:16][C:17]4[CH:18]=[C:19]([CH:25]=[CH:26][CH:27]=4)[C:20]([O:22]CC)=[O:21])=[N:13][C:14]=3[CH:15]=2)=[N:4][N:3]=[N:2]1.C1COCC1.[OH-].[Li+].Cl>O.CO>[NH:1]1[C:5]([C:6]2[CH:7]=[CH:8][C:9]3[C:10]4[S:30][CH:29]=[CH:28][C:11]=4[C:12]([NH:16][C:17]4[CH:18]=[C:19]([CH:25]=[CH:26][CH:27]=4)[C:20]([OH:22])=[O:21])=[N:13][C:14]=3[CH:15]=2)=[N:4][N:3]=[N:2]1
Reactant: CCOC(=O)c1cccc(Nc2nc3cc(-c4nnn[nH]4)ccc3c3sccc23)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cccc(Nc2nc3cc(-c4nnn[nH]4)ccc3c3sccc23)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
ethyl 3-(7-(1H-tetrazol-5-yl)thieno[3,2-c]quinolin-4-ylamino)benzoate (1.0 eq, 7.6 mg, 0.018 mmol) was suspended in a 1:1:1 mixture of THF, MeOH and water. Lithium Hydroxide was added (40 mg, 1.66 mmol) and the mixture stirred at room temperature for one hour. Water and hydrochloric acid were added and the resulting solid filtered and dried to afford 3-(7-(1H-tetrazol-5-yl)thieno[3,2-c]quinolin-4-ylamino)benzoic acid as a solid. LCMS (ES): 95% pure, m/z 389 [M+1]+.
Reaction SMILES: O=[C:2]1[C:7]2[C:8]([C:11]([OH:13])=[O:12])=[CH:9][O:10][C:6]=2[CH2:5][CH2:4][CH2:3]1.Cl.[NH2:15][OH:16].C([O-])(=O)C.[Na+].O>C(O)C>[OH:16]/[N:15]=[C:2]1/[CH2:3][CH2:4][CH2:5][C:6]2[O:10][CH:9]=[C:8]([C:11]([OH:13])=[O:12])[C:7]/1=2
Reactant: NO
Reactant: O=C(O)c1coc2c1C(=O)CCC2
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C(O)c1coc2c1/C(=N\O)CCC2
Yield: 95.4 %

Procedure:
To a solution of 30.0 g of 4,5,6,7-tetrahydro-4-oxo-3-benzofurancarboxylic acid in 225 ml of ethanol is added 22.97 g of hydroxylamine hydrochloride, followed by 18.10 g of sodium acetate and 55 ml of water. The reaction mixture is heated at reflux for 2.5 hours and concentrated in vacuo to a residue which is diluted with 600 ml of ethyl acetate, washed with 2×200 ml of water, brine and dried over Na2SO4. The organic layer is concentrated in vacuo to a residue which is dried under vacuum to give 31.0 g of the desired product as a solid.
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([CH2:21][S:22][CH3:23])[C:17]=3[CH:24]=2)[C:3]1=[O:25].ClC1C=C(C=CC=1)C(OO)=[O:31].C(OCC)(=O)C>C(Cl)Cl>[CH3:1][N:2]1[C:7]([C:8]([F:9])([F:10])[F:11])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([CH2:21][S:22]([CH3:23])=[O:31])[C:17]=3[CH:24]=2)[C:3]1=[O:25]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSCc1nsc2ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(CS(C)=O)c3c2)c1=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of 1-methyl-3-{3-[(methylthio)methyl]-1,2-benzisothiazol-5-yl}-6-(trifluoromethyl)-2,4(1H,3H)-pyrimidinedione (0.740 g, 1.90 mmol) in methylene chloride is treated with 3-chloroperoxybenzoic acid (0.580 g, 60%, 2.00 mmol), stirred at room temperature for five minutes, diluted with additional methylene chloride, washed with 5% sodium carbonate solution, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain a solid. Flash column chromatography of the solid using silica gel and a 10% ethyl acetate in methylene chloride solution gives the title product as a white solid which is identified by NMR spectral analysis.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([OH:12])[CH2:9][C@H:8]1[CH:13]=[C:14]([CH3:18])[C:15](=[O:17])[CH3:16])=[O:6])[CH:2]=[CH2:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:38](O)(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([O:12][C:38](=[O:45])[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:9][C@H:8]1[CH:13]=[C:14]([CH3:18])[C:15](=[O:17])[CH3:16])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C[C@H](O)C[C@H]1C=C(C)C(C)=O
Reactant: O=C(O)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=CCOC(=O)N1C[C@@H](OC(=O)c2ccccc2)C[C@H]1C=C(C)C(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.2 %

Procedure:
To a solution of (2S,4R)-1-allyloxycarbonyl-4-hydroxy-2-(2-methyl-3-oxo-1-butenyl)pyrrolidine (0.33 g), triphenylphosphine (0.52 g) and benzoic acid (0.24 g) in tetrahydrofuran (4 ml) was added diethyl azodicarboxylate (0.31 ml) at ambient temperature. After stirring at ambient temperature for 1 hour, the solution was evaporated. To the residue was added a mixture of n-hexane and ethyl acetate (2:1 V/V), and precipitated triphenylphosphine oxide was filtered off. The filtrate was evaporated, and the residue was chromatographed on silica gel (80 ml) eluting with a mixture of n-hexane and ethyl acetate (8:2-7:3 V/V) to give (2S,4S)-1-allyloxycarbonyl-4-benzoyloxy-2-(2-methyl-3-oxo-1-butenyl)pyrrolidine (0.42 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].[N:6]1[C:13](Cl)=[N:12][C:10](Cl)=[N:9][C:7]=1Cl>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:7]1[N:9]=[CH:10][N:12]=[C:13]([O:5][CH2:4][CH2:3][O:2][CH3:1])[N:6]=1
Reactant: COCCO
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COCCOc1ncnc(OCCOC)n1
Temperature: 110 °C
Yield: 1608.9 %

Procedure:
In 100 ml of dry toluene containing 10 g of anhydrous sodium carbonate was dissolved 20 g of monomethoxypolyethylene glycol having an average molecular, weight of 4000 (Nippon Oil and Fats) and the solution was heated at 110° C. for 30 minutes. Then, 500 mg of cyanuric chloride was added and the mixture was heated at 110° C. for 24 hours. The reaction residue was filtered off, followed by addition of 300 ml of petroleum ether to cause precipitation. The precipitate was washed with several portions of petroleum ether to recover 10 g of 2,4-bis(O-methoxypolyethylene glycol)-6-chloro-s-triazine (yield 50%).
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][C:14]([C:17](OC)=[O:18])=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]([C:7](OC)=[O:8])=[CH:3][CH:2]=1.C1COCC1.O>C(Cl)Cl>[C:11]1([C:1]2[CH:6]=[CH:5][C:4]([CH:7]=[O:8])=[CH:3][CH:2]=2)[CH:16]=[CH:15][C:14]([CH:17]=[O:18])=[CH:13][CH:12]=1
Reactant: COC(=O)c1ccc(-c2ccc(C(=O)OC)cc2)cc1
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=Cc1ccc(-c2ccc(C=O)cc2)cc1
Reaction time: 4.5 h
Yield: 86.1 %

Procedure:
Next, 27.1 g (0.10 mole) of dimethyl 4,4′-biphenyldicarboxylate and 133.4 g of THF were introduced to a 2000-ml four-necked reaction vessel. To this solution was added the reagent solution prepared above in drops at 5° C. or below. After the dropwise addition, stirring was continued at 15° C. for 4.5 hours. Upon completion of the reaction, extraction was performed by adding in drops 622.2 g of methylene chloride and 411.2 g of water. The methylene chloride layer obtained was concentrated until dryness under reduced pressure. The residue was dissolved in acetone by adding 303.2 g of acetone in drops and then 1600.3 g of water was added in drops at 20° C. Thereafter, the mixture was stirred day and night at 5° C. and a solid was recovered by filtration. The solid thus obtained was washed with acetone and dried under reduced pressure to give 18.1 g of 4,4′-biphenyldicarboxaldehyde.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=1)[CH2:3][NH:4][C:5]1[S:6][C:7]([C:10]2[CH:11]=[CH:12][C:13](F)=[C:14]([CH:17]=2)[C:15]#[N:16])=[CH:8][N:9]=1.[NH2:30][NH2:31]>>[NH2:1][C@@H:2]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]([F:28])([F:29])[F:27])=[CH:24][CH:25]=1)[CH2:3][NH:4][C:5]1[S:6][C:7]([C:10]2[CH:17]=[C:14]3[C:13](=[CH:12][CH:11]=2)[NH:31][N:30]=[C:15]3[NH2:16])=[CH:8][N:9]=1
Reactant: N#Cc1cc(-c2cnc(NC[C@@H](N)Cc3ccc(C(F)(F)F)cc3)s2)ccc1F
Reactant: NN
Product: Nc1n[nH]c2ccc(-c3cnc(NC[C@@H](N)Cc4ccc(C(F)(F)F)cc4)s3)cc12
Temperature: 100 °C
Yield: 62 %

Procedure:
5-(2-((S)-2-amino-3-(4-(trifluoromethyl)phenyl)propylamino)thiazol-5-yl)-2-fluorobenzonitrile (0.042 g, 0.100 mmol) was taken up in hydrazine (0.50 mL) in a microwave safe tube. The tube was sealed and heated in a Personal Chemistry microwave unit to 100° C. for 5 minutes. The hydrazine was then removed under reduced pressure, and the residue was purified by HPLC (95:5 to 70:30 water:MeCN over 45 minutes), affording 5-(2-((S)-2-amino-3-(4-(trifluoromethyl)phenyl)propylamino)thiazol-5-yl)-1H-indazol-3-amine (0.027 g, 0.062 mmol, 62% yield) as a yellow amorphous solid. 1H NMR (400 MHz, CD3OD) δ ppm 7.75-7.71 (m, 1H), 7.67-7.60 (m, 2H), 7.51-7.45 (m, 3H), 7.34-7.25 (m, 2H), 3.64-3.48 (m, 2H), 3.42-3.34 (m, 1H), 3.09-3.00 (m, 1H), 2.89 (dd, J=13.8, 7.1 Hz, 1H), 1.95-1.91 (m, 1H). HRMS (M+H) for C25H27F3N6O2S calc. 433.14168, obs. 433.14225.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:12]([O-])=O)[CH:8]=2)[N:3]=1.[CH3:15][O:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:26]=1[CH:25]([NH2:27])[CH2:24][CH2:23][CH2:22]2>>[CH3:15][O:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:26]=1[CH:25]([NH:27][C:2]1[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([NH2:12])[CH:8]=3)[N:3]=1)[CH2:24][CH2:23][CH2:22]2
Reactant: O=[N+]([O-])c1ccc2nc(Cl)ccc2c1
Reactant: COc1cccc2c1C(N)CCC2
Product: COc1cccc2c1C(Nc1ccc3cc(N)ccc3n1)CCC2

Procedure:
The title compound was prepared in accordance with the general method described in example 2 from 2-chloro-6-nitro-quinoline and rac-8-methoxy-1,2,3,4-tetrahydronaphthalen-1-amine (CAS no. 535935-61-6); MS: m/e=320.3 (M+H+).
Reaction SMILES: CC([Si](C)(C)[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][O:16][CH3:17])[C:9]=1[C:18]1([C:21](OCC)=[O:22])[CH2:20][CH2:19]1)(C)C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCCC1>[OH:22][CH2:21][C:18]1([C:9]2[C:10]([O:14][CH2:15][O:16][CH3:17])=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][OH:6])[CH2:19][CH2:20]1
Reactant: CCOC(=O)C1(c2c(CO[Si](C)(C)C(C)(C)C)cccc2OCOC)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COCOc1cccc(CO)c1C1(CO)CC1
Reaction time: 2 h

Procedure:
To a solution of ethyl 1-(2-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)-6-{[(methyloxy)methyl]oxy}phenyl)cyclopropanecarboxylate (Intermediate 133, 780 mg) in dry tetrahydrofuran (20 ml) at 0° C., a solution of LiAlH4 in THF (1M, 2.076 mL, 2.076 mmol) was slowly added and the reaction mixture was stirred for 2 hours at the same temperature. The reaction was quenched with water (10 ml) and brine (10 ml) and diluted with ethyl acetate (30 ml). The solid was filtered off and two phases were separated. The aqueous layer was extracted with ethyl acetate (30 ml) and the combined organic layers were dried over sodium sulphate, filtered and evaporated to afford the alcohol intermediate as a colourless oil. It was dissolved in dry tetrahydrofuran (20.00 mL) and TBAF 1M solution in THF (2.076 mL, 2.076 mmol) was slowly added at 0° C. The reaction mixture was stirred for 1 hour at the same temperature. The reaction was quenched with water (10 ml) and brine (10 ml) and extracted with ethyl acetate (2×30 ml). The organic layer was dried over sodium sulphate, filtered and evaporated and the residue was purified by flash chromatography (Biotage system) on silica gel using a 50 g SNAP column and cyclohexane/ethyl acetate as eluents from 7:3 to 3:7. This afforded the title compound (450 mg) as a white crystal solid.