Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[F:13][C:14]([F:28])([F:27])[C:15]([NH:17][C:18]1[CH:26]=[C:25]2[C:21]([CH2:22][CH:23]=[CH:24]2)=[CH:20][CH:19]=1)=[O:16].Br[CH2:30][C:31]1[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][C:32]=1[O:41][CH3:42].[Cl-].[NH4+]>CCCCCC.O1CCCC1.C(OCC)(=O)C>[CH3:42][O:41][C:32]1[CH:33]=[C:34]([CH:39]=[CH:40][C:31]=1[CH2:30][C:24]1[C:25]2[C:21](=[CH:20][CH:19]=[C:18]([NH:17][C:15](=[O:16])[C:14]([F:27])([F:28])[F:13])[CH:26]=2)[CH2:22][CH:23]=1)[C:35]([O:37][CH3:38])=[O:36]
Reactant: O=C(Nc1ccc2c(c1)C=CC2)C(F)(F)F
Reactant: COC(=O)c1ccc(CBr)c(OC)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(CC2=CCc3ccc(NC(=O)C(F)(F)F)cc32)c(OC)c1
Temperature: -100 °C
Reaction time: 0.25 h
Yield: 14 %

Procedure:
A solution of n-butyllithium in hexane (1.4M, 38.82 ml) was added to a -78° C. solution of diisopropylamine (7.85 ml) in tetrahydrofuran (25 ml). After stirring for 15 min, a solution of 6-(trifluoroacetamido)-3H-indene (5.92 g) in tetrahydrofuran (25 ml) was added and stirred for 1 h. The reaction mixture was cooled to -100° C. and a solution of methyl 4-bromomethyl-3-methoxybenzoate (8.44 g) in tetrahydrofuran (35 ml) was added. The mixture was allowed to warm to room temperature and stirred for 18 h. The reaction mixture was added to saturated ammonium chloride (100 ml) and ethyl acetate (150 ml). The mixture was washed (water, brine), dried (MgSO4) and evaporated. The residue was recrystallized from 10:1 methylene chloride:hexane to give methyl 3-methoxy-4-[6-(trifluoroacetamido)-3H-inden-1-ylmethyl]benzoate (1.48 g, 14%). The residue derived from the filtrate was recrystallized from 3:1 methylene chloride:hexane to give a mixture of methyl 3-methoxy-4-[6-(trifluoroacetamido)-3H-inden-1-ylmethyl]benzoate and methyl 3-methoxy-4-[6-(trifluoroacetamido)-1H-inden-1-ylmethyl]benzoate (1.92 g). This mixture was treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (1.11 g) and tetrahydrofuran (20 ml) for 18 h. After partitioning between ethyl acetate (85 ml) and 1N hydrochloric acid, the organic layer was washed (brine) and dried (MgSO4). Evaporation and trituration with methylene chloride gave a colorless solid. This was combined with the above material to give methyl 3-methoxy-4-[6-(trifluoroacetamido)-3H-inden-1-ylmethyl]-3-methoxybenzoate (2.81 g, 27% total yield from 6-(trifluoroacetamido)-3H-indene); mp 198.5°-200.0° C.; MS(CI), m/e=406(M+H).
Reaction SMILES: [CH2:1]([C@H:8]([CH:12]=[CH2:13])[C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:14]([Si:17]([CH3:20])([CH3:19])[CH3:18])C=C>C(Cl)Cl.CC1C=C(C)C(N2C(=[Ru](Cl)(Cl)=CC3C=CC=CC=3OC(C)C)N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1>[CH2:1]([C@H:8]([CH:12]=[CH:13][CH2:14][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC[Si](C)(C)C
Reactant: C=C[C@@H](Cc1ccccc1)C(=O)O
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2OC(C)C)c(C)c1
Solvent: ClCCl
Product: C[Si](C)(C)CC=C[C@@H](Cc1ccccc1)C(=O)O

Procedure:
To a solution of (2R)-2-benzylbut-3-enoic acid (1.4 mmol, 250 mg) and allyltrimethylsilane (4.2 mmol, 0.67 mL) in DCM (3 mL) at reflux was added Hoveyda-Grubbs second generation catalyst (5 mol %, 44 mg). The reaction was allowed to stir at reflux for 50 hrs. The solvent was removed in vacuo. The crude product was purified by column chromatography (184 mg, 50%). 1H NMR (400 MHz, CDCl3): δ=7.15-7.30 (m, 5H), 5.48-5.56 (m, 1H), 5.26 (dd, J=8.8, 15.2, 1H), 3.30 (m, 1H), 3.10 (dd, J=7.1, 13.9, 1H), 2.80 (dd, J=7.8, 13.6, 1H), 1.43 (d, J=8.3, 2H), −0.08 (s, 9H); 13C NMR (125 MHz, CDCl3): δ=179.5, 138.7, 131.4, 130.1, 129.1, 129.0, 128.3, 126.4, 126.3, 124.3, 123.7, 50.8, 38.5, 22.9, 18.9, −2.08; IR (CHCl3): v 2955, 1797; HMRS required for C15H21O2Si ([M−H]−) 261.1311 found 261.1318; [α]D21=−39.4 (c, 0.5, CHCl3).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH2:10])=[O:9])=[CH:6][CH:5]=1.Cl[C:16]([S:18]Cl)=[O:17]>C1(C)C=CC=CC=1>[F:1][C:2]([F:13])([F:14])[O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]2[O:9][C:16](=[O:17])[S:18][N:10]=2)=[CH:6][CH:5]=1
Reactant: NC(=O)c1ccc(OC(F)(F)F)cc1
Reactant: O=C(Cl)SCl
Solvent: Cc1ccccc1
Product: O=c1oc(-c2ccc(OC(F)(F)F)cc2)ns1
Temperature: 90 °C

Procedure:
To a solution of 4-trifluoromethoxybenzamide (0.50 g, 2.43 mmol) in toluene (10 ml) was added chlorocarbonylsulfenyl chloride (0.50 ml, 6.09 mmol). The resulting reaction mixture was refluxed at 90° C. for 2 h. After the completion of the reaction (TLC monitoring), the mixture was concentrated, added diethyl ether and washed twice with water, twice with 5% NaHCO3, again with water, and was dried (Na2SO4), concentrated under vacuum to give the product (crude yield 0.74 g) that was carried forward to the next step without further purification. MS ES+ (264.18).
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]2[NH:19][CH:20]=[CH:21][C:13]=2[C:12]=1[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH3:29][C:30]1[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1>>[C:1]([O:5][CH:6]([C:11]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]2[N:19]([S:36]([C:33]3[CH:34]=[CH:35][C:30]([CH3:29])=[CH:31][CH:32]=3)(=[O:38])=[O:37])[CH:20]=[CH:21][C:13]=2[C:12]=1[C:22]1[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=1)[C:7]([OH:9])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(Cl)cc2)c2cc[nH]c2c(=O)n1C
Product: Cc1ccc(S(=O)(=O)n2ccc3c(-c4ccc(Cl)cc4)c(C(OC(C)(C)C)C(=O)O)n(C)c(=O)c32)cc1

Procedure:
The title compound was prepared in a manner similar to that described in Example 16 from methyl 2-(tert-butoxy)-2-(4-(4-chlorophenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetate and 4-methylbenzenesulfonyl chloride. 1H NMR (400 MHz, CHLOROFORM-d) ppm 7.98-8.08 (m, 2H) 7.84-7.92 (m, 1H) 7.52-7.59 (m, 1H) 7.43-7.52 (m, 2H) 7.30-7.37 (m, 3H) 6.07-6.17 (m, 1H) 5.21-5.28 (m, 1H) 3.53-3.65 (m, 3H) 3.47-3.63 (m, 3H) 2.42 (s, 3H) 0.98 (s, 9H); LCMS (m/z) ES+=543 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10]C)=[CH:5][CH:4]=1.C[C:14]([O-:16])=[O:15].CC([O-])=O.CC([O-])=O.CC([O-])=O.[Pb+2].C(OC(OCC)OCC)C.Cl(O)(=O)(=O)=O>[OH-].[K+].O.CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([CH3:10])[C:14]([OH:16])=[O:15])=[CH:7][CH:8]=1
Reactant: CCC(=O)c1ccc(OC)cc1
Reactant: CC(=O)[O-]
Agent: [K+]
Agent: [O-][Cl+3]([O-])([O-])O
Agent: [OH-]
Solvent: CO
Solvent: CCOC(OCC)OCC
Solvent: O
Product: COc1ccc(C(C)C(=O)O)cc1
Temperature: 55 °C
Yield: 63.5 %

Procedure:
A mixture of p-methoxypropiophenone (2.39 g, 14.5 mmol), 90%/0 lead(IV)acetate (6.45 g, 14.5 mmol), triethylorthoformate (15 ml) and 70% perchloric acid (1.2 ml. 29 mmol) was heated to 55° C. for 18 h. The mixture was cooled and the triethylorthoformate removed under reduced pressure. The residue was dissolved in CHCl3 and the remaining precipitate filtered off and discarded. The CHCl3 solution was then washed with water and evaporated to yield the crude ester. This crude ester product was dissolved in a 10% KOH 1:1 water:methanol solution which was then refluxed for 3 h. After cooling the methanol was evaporated under reduced pressure and the aqueous solution washed with diethylether (3×25 ml). The aqueous solution was acidified with 2N H2SO4, then washed again with diethylether (3×25 ml). The combined fractions from the second ether wash were dried (Na2SO4) and evaporated to give the propionic acid (1.66 g, 63%).
Reaction SMILES: [CH3:1][CH2:2][C@@:3]1([OH:29])[C:8](=[O:9])[O:7][CH2:6][C:5]2[C:10]([N:12]3[C:16](=[CH:17][C:4]1=2)[C:15]1[N:18]=[C:19]2[C:24](=[CH:25][C:14]=1[CH2:13]3)[C:23]([N+:26]([O-])=O)=[CH:22][CH:21]=[CH:20]2)=[O:11]>[Fe].Cl>[CH3:1][CH2:2][C@@:3]1([OH:29])[C:8](=[O:9])[O:7][CH2:6][C:5]2[C:10]([N:12]3[C:16](=[CH:17][C:4]1=2)[C:15]1[N:18]=[C:19]2[C:24]([C:23]([NH2:26])=[CH:22][CH:21]=[CH:20]2)=[CH:25][C:14]=1[CH2:13]3)=[O:11]
Reactant: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3c([N+](=O)[O-])cccc3nc2-1
Agent: [Fe]
Agent: Cl
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3c(N)cccc3nc2-1

Procedure:
As a specific example, approximately 0.5 g of the 9-nitrocamptothecin derivatives can be mixed with about 100 mg of iron powder and 20 ml of 10% HCl to form the 9-aminocamptothecin derivative.
Reaction SMILES: [CH:1]1([CH2:4][O:5][CH2:6][CH2:7][C:8]2[CH:19]=[CH:18][C:11]([O:12][CH2:13][CH:14]([OH:17])[CH2:15][NH2:16])=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[C:20]([OH:30])(=[O:29])[C@H:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[OH:22]>O.CO>[C:20]([O-:30])(=[O:29])[CH:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[OH:22].[CH:1]1([CH2:4][O:5][CH2:6][CH2:7][C:8]2[CH:9]=[CH:10][C:11]([O:12][CH2:13][CH:14]([OH:17])[CH2:15][NH2:16])=[CH:18][CH:19]=2)[CH2:3][CH2:2]1
Reactant: O=C(O)[C@@H](O)c1ccccc1
Agent: NCC(O)COc1ccc(CCOCC2CC2)cc1
Solvent: CO
Solvent: O
Product: O=C([O-])C(O)c1ccccc1
Reaction time: 0.08 h

Procedure:
(±)-3-[4-(2-(Cyclopropylmethoxy)ethyl)phenoxy]-2-hydroxypropylamine (25 g) was dissolved in hot water (200 ml) and methanol (50 ml). To this solution was added, with vigorous stirring, a solution of L-(+)-mandelic acid (14.35 g) in hot water (200 ml). The mixture was stirred for five minutes, cooled and seeded to give crystals. These were collected and recrystallised three times from hot water to afford a mandelate salt of 3-[4-(2-(cyclopropylmethoxy)ethyl)phenoxy]-2-hydroxypropylamine (5.04 g). To part of this compound (4.54 g) in chloroform (75 ml) was added 15% sodium carbonate solution (75 ml) and the two phase mixture was vigorously stirred at room temperature for one hour. The two layers were separated, the aqueous layer washed with chloroform (3×25 ml) and the organic layer and chloroform washings were combined, dried and evaporated under reduced pressure to give a residue (2.81 g). This residue was dissolved in hot acetonitrile (25 ml), filtered, evaporated to low volume and cooled to afford (-)-3-[4-(2-(cyclopropylmethoxy)ethyl)phenoxy]-2-hydroxypropylamine (2.05 g), [α]D25 =-17.77° [concentration 1.1% in ethanol:water:concentrated HCl (17:2:1)]: nuclear magnetic resonance spectrum consistent with racemic material; identical by chromatography.
Reaction SMILES: C[O:2][C:3](=[O:18])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[OH-].[K+]>C1COCC1.CO>[C:9]1([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:10]=[CH:11][C:6]([CH:5]=[CH:4][C:3]([OH:18])=[O:2])=[CH:7][CH:8]=1
Reactant: COC(=O)C=Cc1ccc(-c2ccccc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C=Cc1ccc(-c2ccccc2)cc1
Reaction time: 3 h
Yield: 83.7 %

Procedure:
To a suspension of 3-biphenyl-4-yl-acrylic acid methyl ester (9.384 g, 39.38 mmol) in THF (120 ml) and MeOH (80 ml) was added 1N KOH (79 ml) and the mixture refluxed. After 3 h, heating was stopped. The reaction mixture was concentrated to about 50 ml, diluted with water (200 ml) and acidified with 2N HCl (80 ml). EtOAc (1000 ml) was added and the whole mixture heated to boiling to dissolve all solids. After cooling, the layers were separated and the organic layer washed with 1N HCl (2×70 ml), water (3×70 ml), brine (2×50 ml), dried over Na2SO4, filtered, concentrated and dried to give 3-biphenyl-4-yl-acrylic acid (7.393 g, 32.966 mmol, 84%) as a white solid, dec. 223-226° C. 1H NMR (DMSO-d6) δ 6.58 (d, 1H), 7.37-7.53 (m, 3H), 7.62 (d, 1H), 7.70-7.84 (m, 6H), 12.40 (s, 1H); mass spectrum [ES(−)], m/z 223 (M−H)−.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.C(N(CC)CC)C.Cl[C:23]([O:25][C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=1)=[O:24]>C(Cl)Cl>[N+:32]([C:29]1[CH:30]=[CH:31][C:26]([O:25][C:23]([O:1][CH:2]2[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]2)=[O:24])=[CH:27][CH:28]=1)([O-:34])=[O:33]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(OC(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.2 %

Procedure:
To a mixture of tert-butyl 4-hydroxypiperidine-1-carboxylate (0.30 g, 0.0015 mol) (Aldrich Cat. #495484) and triethylamine (0.31 mL, 0.0022 mol) in methylene chloride (2 mL) was added p-nitrophenyl chloroformate (0.33 g, 0.0016 mol) (Acros Organics, Cat. #17080). The mixture was stirred at r.t. for 2 h. After removal of the solvent under reduced pressure, the residue was purified by flash chromatography on a silica gel with ethyl acetate in hexanes (0-20%) to afford the desired product (0.32 g, 58%). Analytic LCMS (M+Na)+: m/z=389.0.
Reaction SMILES: C(O[CH:4]=[CH:5][C:6]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)=O)C.[NH2:14][C:15]1[C:19]([C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:21])=[CH:18][NH:17][N:16]=1>C1(C)C(C)=CC=CC=1>[C:22]1([C:20]([C:19]2[CH:18]=[N:17][N:16]3[C:6]([C:8]4[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=4)=[CH:5][CH:4]=[N:14][C:15]=23)=[O:21])[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Nc1n[nH]cc1C(=O)c1ccccc1
Reactant: CCOC=CC(=O)c1cccnc1
Solvent: Cc1ccccc1C
Product: O=C(c1ccccc1)c1cnn2c(-c3cccnc3)ccnc12

Procedure:
A mixture of 0.02 mole of 3-ethoxy-1-(3-pyridinyl)-2-propen-1-one, 0.02 mole of (3-amino-1H-pyrazol-4-yl)phenyl-methanone and 100 ml of xylene was refluxed for 12 hours. The solvent was removed and the residue dissolved in dichloromethane. This solution was dried over sodium sulfate and the product isolated as described in Example 1, as crystals, mp 202°-203° C.
Reaction SMILES: [C:1]([CH2:4][N:5]([CH2:10][CH2:11][N:12]([CH2:26][C:27]([OH:29])=[O:28])[CH2:13][CH2:14][N:15]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:16][C:17]([OH:19])=[O:18])[CH2:6][C:7]([OH:9])=O)([OH:3])=[O:2].N1C=CC=CC=1>C(OC(=O)C)(=O)C>[O:9]=[C:7]1[CH2:6][N:5]([CH2:10][CH2:11][N:12]([CH2:13][CH2:14][N:15]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:16][C:17]([OH:19])=[O:18])[CH2:26][C:27]([OH:29])=[O:28])[CH2:4][C:1](=[O:2])[O:3]1
Reactant: CCOC(=O)CN(CCN(CCN(CC(=O)O)CC(=O)O)CC(=O)O)CC(=O)O
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)CN(CCN(CCN1CC(=O)OC(=O)C1)CC(=O)O)CC(=O)O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A suspension of 21.1 g (50 mmol) of N3,N6-bis(carboxymethyl)-N9-(ethoxy-carbonylmethyl)-3,6,9-triazaundecanedioic acid in 250 ml of acetic anhydride is allowed to stir for three days at room temperature after the addition of 42.2 ml of pyridine. Then, the precipitate is suctioned off, washed three times with 50 ml of acetic anhydride each and then stirred for several hours with absolute diethyl ether. After suctioning off, washing with absolute diethyl ether and drying in a vacuum at 40° C., 18.0 g (=89% of theory) of a white powder with a melting point of 195-196° C. is obtained.
Reaction SMILES: Cl.C([O:9][CH2:10][C:11]1[N:12]([CH2:28][CH2:29][OH:30])[C:13]([S:19][C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=2)=[C:14]([CH:16]([CH3:18])[CH3:17])[N:15]=1)C1C=CC=CC=1.C(=O)([O-])O.[Na+]>>[Cl:27][C:22]1[CH:21]=[C:20]([S:19][C:13]2[N:12]([CH2:28][CH2:29][OH:30])[C:11]([CH2:10][OH:9])=[N:15][C:14]=2[CH:16]([CH3:18])[CH3:17])[CH:25]=[C:24]([Cl:26])[CH:23]=1
Reactant: CC(C)c1nc(COCc2ccccc2)n(CCO)c1Sc1cc(Cl)cc(Cl)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(C)c1nc(CO)n(CCO)c1Sc1cc(Cl)cc(Cl)c1
Temperature: 110 °C
Yield: 66.4 %

Procedure:
Added was 18 ml of cocentrated hydrochloric acid to 1.8 g (4.0 mmol) of the alcohol compound (118c), and the mixture was stirred with heating at 110° C. for 7 hours. After cooling, the mixture was neutralized with sodium hydrogen carbonate, and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give 960 mg of 2-(5-(3,5-dichlorophenyl-thio)-2-hydroxymethyl-4-isopropyl-1H-imidazol-1-yl)ethanol (119b) as oil (yield 67%).
Reaction SMILES: [CH3:1][C:2]1([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:7][CH2:6][CH:5]([C:8]2[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.C(C1CCC(C2C=CC=CC=2)CC1)#N.[Li+].CC([N-]C(C)C)C.C(Br)CCCCCC.CC(C[AlH]CC(C)C)C.NN.[CH2:62]([CH:68]([CH2:71]O)[CH2:69][OH:70])[CH2:63][CH2:64][CH2:65][CH2:66][CH3:67].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.O>[CH3:1][C:2]1([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:7][CH2:6][CH:5]([C:8]2[CH:9]=[CH:10][C:11]([CH:12]3[O:70][CH2:69][CH:68]([CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH3:67])[CH2:71][O:13]3)=[CH:14][CH:15]=2)[CH2:4][CH2:3]1
Reactant: CCCCCC1(C)CCC(c2ccc(C=O)cc2)CC1
Reactant: CCCCCCC(CO)CO
Agent: CC(C)C[AlH]CC(C)C
Agent: CC(C)[N-]C(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCCCCCCBr
Solvent: Cc1ccccc1
Product: CCCCCCC1COC(c2ccc(C3CCC(C)(CCCCC)CC3)cc2)OC1

Procedure:
27.2 g (0.1 mole) of p-(4-methyl-4-pentylcyclohexyl)-benzaldehyde (obtainable from 4-cyanocyclohexylbenzene by alkylation with LDA and heptyl bromide, stepwise conversion of the nitrile group into the methyl group by reduction with DIBAH and hydrazine in a Wolff-Kishner reaction and introduction of the formyl group by chloromethylation and a Sommelet reaction) are boiled with 16.0 g (0.1 mole) of 2-hexylpropane-1,3-diol and 0.1 g of p-toluenesulfonic acid in 150 ml of toluene, using a water separator, until no further water of reaction is formed. The cooled reaction mixture is washed twice with 5% NaHCO3 solution (100 ml each time) and then with water and dried. After the solvent has been evaporated off, the residue is recrystallised from ethanol. p-(4-Methyl-4-pentylcyclohexyl)-(5-hexyl-1,3-dioxan-2-yl)-benzene is obtained.
Reaction SMILES: [F:1][C:2]1[C:3]2[C:4](=[C:21]([CH3:24])[O:22][N:23]=2)[N:5]=[C:6]([C:17]([O:19]C)=[O:18])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=1[F:16].[Li+].[OH-]>C1COCC1.O>[F:1][C:2]1[C:3]2[C:4](=[C:21]([CH3:24])[O:22][N:23]=2)[N:5]=[C:6]([C:17]([OH:19])=[O:18])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=1[F:16]
Reactant: COC(=O)c1nc2c(C)onc2c(F)c1Nc1ccc(I)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1onc2c(F)c(Nc3ccc(I)cc3F)c(C(=O)O)nc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of methyl 7-fluoro-6-(2-fluoro-4-iodophenylamino)-3-methylisoxazolo[4,3-b]pyridine-5-carboxylate (250 mg, 0.56 mmol) in a mixture of THF (10 ml) and H2O (5 ml) is added a solution of LiOH (67 mg, 2.8 mmol) in H2O (2.4 ml). After stirring at room temperature for 4 h, the reaction is concentrated, acidified with 1 M HCl solution, and extracted with EtOAc (2×20 ml). The organic solution is dried over MgSO4 and concentrated to give the title compound.
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[N:20]([CH3:21])[N:19]=[CH:18][C:17]=2[NH:22][C:23]([C:25]2[N:26]=[C:27](Br)[S:28][C:29]=2[NH:30]C(=O)OC(C)(C)C)=[O:24])[CH2:12][CH2:11]1)=O)CCC.[CH3:39][N:40]([CH3:50])[C:41]1[CH:42]=[C:43](B(O)O)[CH:44]=[CH:45][CH:46]=1>>[NH2:30][C:29]1[S:28][C:27]([C:45]2[CH:44]=[CH:43][CH:42]=[C:41]([N:40]([CH3:50])[CH3:39])[CH:46]=2)=[N:26][C:25]=1[C:23]([NH:22][C:17]1[CH:18]=[N:19][N:20]([CH3:21])[C:16]=1[N:13]1[CH2:12][CH2:11][CH:10]([CH2:9][NH2:8])[CH2:15][CH2:14]1)=[O:24]
Reactant: CN(C)c1cccc(B(O)O)c1
Reactant: CCCCOC(=O)NCC1CCN(c2c(NC(=O)c3nc(Br)sc3NC(=O)OC(C)(C)C)cnn2C)CC1
Product: CN(C)c1cccc(-c2nc(C(=O)Nc3cnn(C)c3N3CCC(CN)CC3)c(N)s2)c1
Yield: 37 %

Procedure:
Following Example 278, Suzuki coupling of tert-butyl 4-(5-(4-(butyloxycarbonylaminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-bromothiazol-5-ylcarbamate and 3-(dimethylamino)phenylboronic acid gave 276 as an off-white solid (34 mg, 37% over two steps). 1H NMR (400 MHz, d4-MeOD) δ 7.37-7.34 (m, 1H), 7.30 (s, 1H), 7.26 (t, J=8.0 Hz, 1H), 7.07 (d, J=7.6 Hz, 1H), 6.82 (dd, J=8.3, 2.6 Hz, 1H), 3.69 (s, 3H), 3.13-3.04 (m, 4H), 2.97 (s, 6H), 2.58 (d, J=6.5 Hz, 2H), 1.80 (d, J=12.5 Hz, 2H), 1.52-1.39 (m, 1H), 1.32 (qd, J=11.8, 4.7 Hz, 2H). LCMS (ES+) m/z 455 (M+1)
Reaction SMILES: Cl[S:2]([C:5]1[CH:19]=[CH:18][C:8]([O:9][C:10]([CH3:17])([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][CH:6]=1)(=O)=O.CCO.[Sn].Cl>C(Cl)Cl>[CH3:17][C:10]([O:9][C:8]1[CH:7]=[CH:6][C:5]([SH:2])=[CH:19][CH:18]=1)([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: [Sn]
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)C(C)(C)Oc1ccc(S)cc1
Yield: 72.2 %

Procedure:
To a 3-L three-neck round-bottom flask equipped with an overhead mechanical stirrer, addition funnel and a N2 inlet was added ethyl 2-[4-(chlorosulfonyl)phenoxy]-2-methylpropanoate (53 g, 0.173 moles, 1 eq) and absolute EtOH (500 ml). Tin powder (325 mesh, 123.06 g, 1.04 moles, 6 eq) was added as a solid. The overhead stirrer was adjusted so that the rotor is as close as possible to the bottom of the round-bottom flask and stirring speed was accelerated to a very high setting before adding the HCl to prevent the clumping of the tin metal. Hydrogen chloride (4N in dioxane, 300 ml) was added dropwise over the course of 1 hour. The reaction mixture was refluxed for 4 hours at which point the hot ethanolic solution was poured into a 2-L Erlenmeyer flask containing CH2Cl2 (1 L) and ice. After stirring for 10 minutes the biphasic mixture was filtered through Celite. After transferring to a separatory funnel the phases were separated and the aqueous fraction was washed with CH2Cl2 (2×100 ml). The combined organic fractions were dried over Na2SO4, filtered and concentrated in vacuo. A bright yellow oil with a white precipitate suspended resulted. This yellow mixture was dissolved in a minimum amount of CH2Cl2 and filtered once again through Celite to yield 30 g (75%) of a bright yellow oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[N:7]([C@@H:18]1[CH2:22][CH2:21][CH2:20][C@H:19]1[NH2:23])[CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:25][S:26]([C:29]1[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=1)(=[O:28])=[O:27].C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:24])[N:7]([CH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=1)[C@@H:18]1[CH2:22][CH2:21][CH2:20][C@H:19]1[NH:23][C:33](=[O:34])[C:32]1[CH:31]=[CH:30][C:29]([S:26]([CH3:25])(=[O:28])=[O:27])=[CH:37][CH:36]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(CCCc1ccc(Cl)cc1)[C@@H]1CCC[C@H]1N
Reactant: CS(=O)(=O)c1ccc(C(=O)O)cc1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(CCCc1ccc(Cl)cc1)[C@@H]1CCC[C@H]1NC(=O)c1ccc(S(C)(=O)=O)cc1
Yield: 106.2 %

Procedure:
Using General Procedure C, (±)-trans-(2-aminocyclopentyl)-[3-(4-chloro-phenyl)propyl]carbamic acid tert-butyl ester (155 mg, 0.44 mmol) and 4-methanesulfonylbenzoic acid (105 mg, 0.53 mmol) were coupled in CH2Cl2 (3 mL) using HOBt (12 mg, 0.09 mmol) and DEC (106 mg, 0.66 mmol) at 0° C. for 2.5 hours to give 250 mg of (±)-trans-[3-(4-chlorophenyl)propyl]-[2-(4-methanesulfonylbenzoylamino)cyclopentyl]carbamic acid tert-butyl ester as a colorless oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([N+:15]([O-])=O)[CH:12]=[CH:11][C:10]=2[CH3:18])[N:5]=[C:4]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[CH:3]=1.O.C(O)C>[Pd].C(N(CC)CC)C>[CH3:18][C:10]1[CH:11]=[CH:12][C:13]([NH2:15])=[CH:14][C:9]=1[NH:8][C:6]1[N:5]=[C:4]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[CH:3]=[CH:2][N:7]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1Nc1nc(Cl)cc(-c2cccnc2)n1
Agent: [Pd]
Solvent: O
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1ccc(N)cc1Nc1nccc(-c2cccnc2)n1
Reaction time: 40 h

Procedure:
In an autoclave, 5 g 6-chloro-N-(2-methyl-5-nitrophenyl)-4-(3-pyridyl)-2-pyrimidine amine, 0.5 g palladium on charcoal 5% wet with 50% water, 50 mL ethanol and 5 mL triethylamine is charged. The mixture is hydrogenated at 5 bars and room temperature for 40 hours. Once completed the conversion, the catalyst is filtered off and the filtrates is concentrated in vacuum. The residue is taken again with isopropyl acetate and an aqueous carbonate solution. The layers are separated, and the organic layer is concentrated, yielding, upon drying, 3 g of product with 85% HPLC purity (A %), which is identified through LC-MS and 1H-NMR.