Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([Br:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N:13]([O-])=O.[Na+].O.O.[Sn](Cl)[Cl:20]>Cl.O>[ClH:20].[Br:11][C:9]1[C:8]([F:12])=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([NH:1][NH2:13])[CH:10]=1
Reactant: Cl[Sn]Cl
Reactant: Nc1cc(Br)c(F)cc1C(=O)O
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NNc1cc(Br)c(F)cc1C(=O)O
Reaction time: 0.5 h
Yield: 44 %

Procedure:
A suspension of 2-amino-4-bromo-5-fluorobenzoic acid (10.0 g, 42.7 mmol) in a mixture of 37% aqueous HCl (42.7 mL) and water (14.3 mL), cooled with a NaCl -ice bath, was treated dropwise with a solution of sodium nitrite (3.24 g, 47.0 mmol) in water (15.7 mL). When addition was complete, the mixture was stirred for 30 min more. A solution of tin(II) chloride dihydrate (28.9 g, 128 mmol) in 37% aqueous HCl (27.5 mL) was added dropwise. The cooling bath was removed and the mixture was stirred at room temperature for 45 min. The thick suspension was filtered and the collected precipitate was washed thoroughly with water and dried overnight under reduced pressure. The solid was triturated with MeOH with sonication, and the precipitate was collected by filtration, washed with MeOH and dried. The filtrate was concentrated, and the residue was triturated with DCM. The resulting solid was collected by filtration, dried and combined with the other solid to give 4-bromo-5-fluoro-2-hydrazinylbenzoic acid hydrochloride (5.37 g, 44% yield) as a white solid. Mass spectrum m/z 249, 251 (M+H)+.
Reaction SMILES: Cl[C:2]([O:4][C:5](Cl)(Cl)Cl)=[O:3].N1C=CC=CC=1.[C:15]([C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH:27]([OH:35])[CH2:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:21][C:20]=1[NH:36][C:37](=[O:53])[CH2:38][CH:39]1[C:52]2[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=2[O:46][C:45]2[C:40]1=[CH:41][CH:42]=[CH:43][CH:44]=2)([CH3:18])([CH3:17])[CH3:16].OC[C:56]([O:58][CH2:59][C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)=[O:57]>O1CCCC1.C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:15]([C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH:27]([O:35][C:2]([O:4][CH2:5][C:56]([O:58][CH2:59][C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)=[O:57])=[O:3])[CH2:28][CH:29]2[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]2)=[CH:21][C:20]=1[NH:36][C:37](=[O:53])[CH2:38][CH:39]1[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:45]=2[O:46][C:47]2[C:52]1=[CH:51][CH:50]=[CH:49][CH:48]=2)([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)c1ccc(CCC(O)CC2CCCCC2)cc1NC(=O)CC1c2ccccc2Oc2ccccc21
Reactant: O=C(CO)OCc1ccccc1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)c1ccc(CCC(CC2CCCCC2)OC(=O)OCC(=O)OCc2ccccc2)cc1NC(=O)CC1c2ccccc2Oc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 158.1 %

Procedure:
A solution of 55 μl (0.46 mmol) of trichloromethyl chloroformate in 1 ml of tetrahydrofuran was added dropwise to a solution of 74 μl (0.91 mmol) of pyridine in 1 ml of tetrahydrofuran, whilst ice-cooling, and then the temperature of the resulting mixture was allowed to rise gradually to room temperature. The mixture was stirred for 1 hour at room temperature, after which it was again cooled, and a solution of 400 mg (0.76 mmol) of N-[2-t-butyl-5-(4-cyclohexyl-3-hydroxybutyl)phenyl]-2-(9H-xanthen-9-yl)acetamide (prepared as described in Example 12) in 3 ml of tetrahydrofuran was added dropwise. The mixture was stirred for 1 hour at the same temperature, and then the solvent was removed by distillation under reduced pressure, to give a colorless foam-like material as a residue. This residue was dissolved in 1 ml of methylene chloride, and a solution of 151 mg (0.91 mmol) of benzyl α-hydroxyacetate in 1.5 ml of methylene chloride and then 110 mg (0.91 mmol) of 4-(N,N-dimethylamino)pyridine were added dropwise, whilst ice-cooling. The mixture was stirred at room temperature for 1 hour, and then the reaction mixture was diluted with methylene chloride, after which it was washed with water and with a saturated aqueous solution of sodium chloride, in that order. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through 75 g of silica gel, using a 1:9 by volume mixture of methylene chloride and ethyl acetate as the eluent, to give 522 mg (yield 96%) of the title compound as a colorless foam-like material.
Reaction SMILES: Br[C:2]1[C:3](=[O:18])[N:4]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)[C:5]([CH3:9])=[CH:6][C:7]=1[OH:8].C(N(CC)CC)C>ClCCl>[F:17][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=1)[CH2:10][N:4]1[C:5]([CH3:9])=[CH:6][C:7]([OH:8])=[CH:2][C:3]1=[O:18]
Reactant: Cc1cc(O)c(Br)c(=O)n1Cc1cccc(F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(O)cc(=O)n1Cc1cccc(F)c1
Temperature: -30 °C
Reaction time: 1 h
Yield: 153.1 %

Procedure:
To a suspension of 3-bromo-1-(3-fluorobenzyl)-4-hydroxy-6-methylpyridin-2(1H)-one (0.86 g, 0.0028 mol) in dichloromethane (15.0 mL) cooled to −30° C., triethyl amine (0.5 mL, 0.004 mol) and trflic anhydride (0.7 mL, 0.0042 mol) were added and stirred for 1 h. The resulting orange solution was poured into ice cold water (25 mL) and extracted with dichloromethane (2×25 mL) The combined organic extracts were washed with water, dried (Na2SO4) and concentrated under reduced pressure. The resulting residue was purified by silica gel flash chromatography using 1:1 EtOAc/hexane v/v to afford 1.0 g (85%) the title compound as a light brown solid: 1H-NMR (CDCl3/400 MHz) δ 7.32 (m, 1H), 7.0-6.85 (m, 3H), 6.18 (s, 1H), 5.32 (s, 2H), and 2.34 (s, 3H); ES HRMS m/z 443.9492 (M+H C14H11NO4BrF4S requires 443.9528). Step 4: Preparation of 3-bromo-1-(3-fluorobenzyl)-6-methyl-4-(phenylethynyl)pyridin-2(1H)-one
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.C(O[CH:19](N(CCC)CCC)[N:20]([CH2:24][CH2:25][CH3:26])[CH2:21][CH2:22][CH3:23])(C)(C)C>O1CCCC1>[CH2:21]([N:20]([CH2:24][CH2:25][CH3:26])[CH:19]=[CH:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2)[CH2:22][CH3:23]
Reactant: CCCN(CCC)C(OC(C)(C)C)N(CCC)CCC
Reactant: Cc1ccc([N+](=O)[O-])c2[nH]ncc12
Solvent: C1CCOC1
Product: CCCN(C=Cc1ccc([N+](=O)[O-])c2[nH]ncc12)CCC
Yield: 90.7 %

Procedure:
2.1 g of 4-methyl-7-nitro-1H-indazole and 5.0 g of tert-butoxybis(dipropylamino)methane are heated to 80° C. in 10 ml of tetrahydrofuran for 2.5 hours. The mixture is concentrated, distilled with tetrahydrofuran, and recrystallized from dichloromethane/hexane, yielding 3.1 g of N,N-dipropyl-N-[2-(7-nitro-1H-indazol-4-yl)ethenyl]amine, mp 166°-167° C.
Reaction SMILES: [NH2:1][C@@:2]1([CH2:9][C:10]#[C:11][C:12]2[CH:17]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([F:28])([F:27])[F:26])[CH:19]=3)[CH:15]=[CH:14][N:13]=2)[CH2:6][CH2:5][N:4]([CH3:7])[C:3]1=[O:8].N>CC#N.CO.CCOC(C)=O.FC(F)(F)S([O-])(=O)=O.[Ag+]>[CH3:7][N:4]1[CH2:5][CH2:6][C@:2]2([N:1]=[C:11]([C:12]3[CH:17]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([F:28])([F:27])[F:26])[CH:19]=4)[CH:15]=[CH:14][N:13]=3)[CH2:10][CH2:9]2)[C:3]1=[O:8]
Reactant: CN1CC[C@@](N)(CC#Cc2cc(-c3cccc(OC(F)(F)F)c3)ccn2)C1=O
Agent: [Ag+]
Agent: N
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CC#N
Product: CN1CC[C@@]2(CCC(c3cc(-c4cccc(OC(F)(F)F)c4)ccn3)=N2)C1=O
Reaction time: 18 h
Yield: 74.1 %

Procedure:
Silver trifluoromethanesulphonate (564.86 mg, 2.2 mmol) was added to a solution of (3S)-3-amino-1-methyl-3-[3-[4-[3-(trifluoromethoxy)phenyl]-2-pyridyl]prop-2-ynyl]pyrrolidin-2-one (which may be prepared as described in Description 11) (4.28 g, 10.99 mmol) in MeCN (60 mL) at 40° C. and the reaction was stirred for 18 hours. Additional AgOTf (10 mol %) was added and stirring was continued for 24 hrs. The solvent was evaporated and the residue was suspended in EtOAc. The organic phase was washed with water, dried (Na2SO4) and the solvent evaporated to afford a light brown oil. This was purified using an Isolera, with a (50+100) g SNAP cartridge, eluting with 0 to 100% (mixture of 1% of 2M NH3 in MeOH; 9% MeOH; 90% EtOAc) in EtOAc affording the (5S)-7-methyl-2-[4-[3-(trifluoromethoxy)phenyl]-2-pyridyl]-1,7-diazaspiro[4.4]non-1-en-6-one (D12) (3.17 g, 8.1414 mmol, 74.1% yield) as a light brown solid;
Reaction SMILES: [CH3:1][C:2]1([CH3:40])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@H:12]3[O:16][C:15](=[O:17])[N:14]([CH2:18][CH2:19][C:20]4[CH:39]=[CH:38][C:23]([O:24][CH2:25][CH2:26][O:27][CH2:28][C:29]5[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=5)[C:32](O)=[O:33])=[CH:22][CH:21]=4)[CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1.[CH:41]([NH2:44])([CH3:43])[CH3:42].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C=O)C.CCOC(C)=O>[CH3:1][C:2]1([CH3:40])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@H:12]3[O:16][C:15](=[O:17])[N:14]([CH2:18][CH2:19][C:20]4[CH:39]=[CH:38][C:23]([O:24][CH2:25][CH2:26][O:27][CH2:28][C:29]5[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=5)[C:32]([NH:44][CH:41]([CH3:43])[CH3:42])=[O:33])=[CH:22][CH:21]=4)[CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1
Reactant: CC(C)N
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCc4ccc(OCCOCc5cccc(C(=O)O)c5)cc4)C(=O)O3)ccc2O1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)NC(=O)c1cccc(COCCOc2ccc(CCN3C[C@@H](c4ccc5c(c4)COC(C)(C)O5)OC3=O)cc2)c1
Reaction time: 8 h
Yield: 115.9 %

Procedure:
A solution of 3-{[2-(4-{2-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]ethyl}phenoxy)ethoxy]methyl}benzoic acid (90 mg) and isopropyl amine (9.7 mg) in DMF (2 ml) was cooled to 0° C. and treated with diisopropylethylamine (0.057 ml) and O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU) (62 mg). This was then stirred for 8 h before diluting in EtOAc and washing sequentially with 2M HCl, NaHCO3 (aq) and brine. The combined organic layers were then dried (MgSO4) and concentrated in vacuo to give the title compound(112 mg). LCMS RT=3.36 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[S:14][C:15]([CH2:17]O)=[CH:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(=O)[NH:42]C(=O)C2=CC=CC=C12.N(C(OCC)=O)=NC(OCC)=O.O.NN>O1CCCC1.C(O)C>[NH2:42][CH2:17][C:15]1[S:14][C:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][C:10]=2[CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCc2sc(CO)cc2C1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: NN
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCc2sc(CN)cc2C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
In tetrahydrofuran (100 ml), 5-tert-butoxycarbonyl-2-hydroxymethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (WO94/21599) (2.10 g) was dissolved. After the addition of triphenylphosphine (2.66 g) and phthalimide (1.15 g), diethyl azodicarboxylate (1.28 ml) was added dropwise, followed by stirring at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (hexane:ethyl acetate=4:1), whereby a colorless solid was obtained. The resulting solid was dissolved in ethanol (40 ml), followed by the addition of hydrazine hydrate (0.39 ml). The resulting mixture was heated under reflux for 5 hours. The precipitate was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (dichloromethane˜dichloromethane:methanol=25:1), whereby the title compound (448 mg, 21%) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-])=O)[C:9]2=[O:17])=[CH:4][CH:3]=1.[Cl-].[NH4+]>C1COCC1.CO.CCOC(C)=O.[Zn]>[NH2:14][C:10]1[C:9](=[O:17])[N:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: O=c1c([N+](=O)[O-])cccn1-c1ccc(F)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1cccn(-c2ccc(F)cc2)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.8 %

Procedure:
To a solution of 1-(4-fluorophenyl)-3-nitropyridin-2(1H)-one (610 mg, 2.6 mmol) from 1a-1 in THF (50 mL) and MeOH (50 mL), were added ammonium chloride (695 mg, 13.0 mmol, EMD) and Zn dust (850 mg, 13.0 mmol, Aldrich). The reaction mixture was stirred at room temperature for 3 h, diluted with 200 mL of EtOAc and filtered through a pad of Celite. The filtrate was concentrated in vacuo to give 3-Amino-1-(4-fluorophenyl)pyridin-2(1H)-one (530 mg, 100% yield) as a brown solid.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[S:5][C:6]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]3[CH:18]=[C:19]([CH:25]=[CH:26][CH:27]=3)[CH2:20][NH:21]C(=O)C)[N:11]=2)=[C:7]([CH3:9])[N:8]=1)[CH3:2]>CC#N>[NH2:21][CH2:20][C:19]1[CH:18]=[C:17]([NH:16][C:12]2[N:11]=[C:10]([C:6]3[S:5][C:4]([NH:3][CH2:1][CH3:2])=[N:8][C:7]=3[CH3:9])[CH:15]=[CH:14][N:13]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: CCNc1nc(C)c(-c2ccnc(Nc3cccc(CNC(C)=O)c3)n2)s1
Solvent: CC#N
Product: CCNc1nc(C)c(-c2ccnc(Nc3cccc(CN)c3)n2)s1

Procedure:
By hydrolysis of N-{3-[4-(2-ethylamino-4-methyl-thiazol-5-yl)-pyrimidin-2-ylamino]-benzyl}-acetamide. Yellow solid. Mp 290-292° C. Anal. RP-HPLC: tR=10.6 min (10-70% MeCN, purity >95%). 1H-NMR (DMSO-D6) δ: 1.31 (t, 3H, J=7.0 Hz, CH3), 2.64 (s, 3H, CH3), 3.54 (m, 2H, CH2), 4.11 (m, 2H, CH2), 7.14 (d, 1H, J=6.0 Hz, pyrimidinyl-H), 7.22 (d, 1H, J=8.0 Hz, Ph-H), 7.45 (t, 1H, J=8.0 Hz, Ph-H), 7.74 (d, 1H, J=8.0 Hz, Ph-H), 7.95 (s, 1H, Ph-H), 8.53 (d, 1H, J=6.0 Hz, pyrimidinyl-H). MS (ESI+) m/z 341.20 [M+H]+ (C17H20N6S requires 340.45).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:17])[C:5]([NH:8][C:9](=[O:16])[CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:6][CH:7]=1.[C:18]([Si:20]([CH3:23])([CH3:22])[CH3:21])#[CH:19].N1CCCCC1>C1COCC1.O.[Cu]I>[CH3:17][C:4]1[C:5]([NH:8][C:9](=[O:16])[CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:6][CH:7]=[C:2]([C:19]#[C:18][Si:20]([CH3:23])([CH3:22])[CH3:21])[CH:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: Cc1cc(Br)cnc1NC(=O)CN1CCCC1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: O
Solvent: C1CCNCC1
Product: Cc1cc(C#C[Si](C)(C)C)cnc1NC(=O)CN1CCCC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Under an argon atmosphere 35 mg (0.03 mmol) tetrakis-triphenylphosphane-palladium and 5.7 mg (0.03 mmol) CuI are added to a solution of 447 mg (1.5 mmol) N-(5-bromo-3-methyl-pyridin-2-yl)-2-pyrrolidin-1-yl-acetamide and 0.23 mL (1.65 mmol) ethynyl-trimethyl-silane in 0.45 mL (4.5 mmol) piperidine and 10 mL THF and the reaction mixture is stirred for 14 h at RT. To complete the reaction a further 35 mg tetrakis-triphenylphosphane-palladium are added and the reaction mixture is heated to 50° C. for 4 h. It is diluted with water, extracted exhaustively with EtOAc, the combined organic phases are washed with saturated NaCl solution and dried over Na2SO4. After the desiccant and solvent have been eliminated the residue is purified by chromatography (silica gel, EtOAc/MeOH/NH3 90:10:1).
Reaction SMILES: [NH2:1][C:2]1[N:7]([C:8]2[C:22]([F:23])=[CH:21][C:11]([O:12][CH2:13][CH2:14][CH2:15]OS(C)(=O)=O)=[CH:10][C:9]=2[F:24])[C:6](=[O:25])[CH:5]=[CH:4][C:3]=1[C:26](=[O:34])[C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1.S(C1C=CC(C)=CC=1)(O)(=O)=O.[CH:46]1([O:51][C:52](=[O:62])[C@H:53]([CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58]C=2)[NH2:54])[CH2:50][CH2:49][CH2:48][CH2:47]1>>[NH2:1][C:2]1[N:7]([C:8]2[C:22]([F:23])=[CH:21][C:11]([O:12][CH2:13][CH2:14][CH2:15][NH:54][C@@H:53]([C:55]3[CH:56]=[CH:61][CH:60]=[CH:59][CH:58]=3)[C:52]([O:51][CH:46]3[CH2:47][CH2:48][CH2:49][CH2:50]3)=[O:62])=[CH:10][C:9]=2[F:24])[C:6](=[O:25])[CH:5]=[CH:4][C:3]=1[C:26](=[O:34])[C:27]1[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)OC1CCCC1
Reactant: CS(=O)(=O)OCCCOc1cc(F)c(-n2c(N)c(C(=O)c3ccc(F)cc3)ccc2=O)c(F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: Nc1c(C(=O)c2ccc(F)cc2)ccc(=O)n1-c1c(F)cc(OCCCN[C@H](C(=O)OC2CCCC2)c2ccccc2)cc1F

Procedure:
From Intermediate 4E and L-phenylalanine cyclopentyl ester tosylate salt (Intermediate 16), LCMS purity 97%, m/z 634 [M+H]+, 1H NMR (400 MHz, CD3OD), δ: 1.30-2.00 (8H, m), 2.30 (2H, m), 3.10 (1H, m), 3.40 (1H, m), 4.25 (2H, m), 4.40 (1H, m), 5.20 (1H, m), 5.85 (1H, d), 6.90 (2H, m), 7.10 (2H, d), 7.20-7.45 (7H, m), 7.65 (2H, m), 7.75 (1H, m).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[CH:8]=[C:9]([Cl:25])[CH:10]=[C:11]3[CH2:16][CH2:15][CH:14]([CH2:17][C:18]([O:20]C(C)(C)C)=[O:19])[C:13]=1[C:12]=23)=[O:4].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[CH:8]=[C:9]([Cl:25])[CH:10]=[C:11]3[CH2:16][CH2:15][CH:14]([CH2:17][C:18]([OH:20])=[O:19])[C:13]=1[C:12]=23)=[O:4]
Reactant: COC(=O)c1[nH]c2cc(Cl)cc3c2c1C(CC(=O)OC(C)(C)C)CC3
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1[nH]c2cc(Cl)cc3c2c1C(CC(=O)O)CC3
Yield: 114.2 %

Procedure:
A mixture of 7-chloro-3-tert-butoxycarbonylmethyl-1,3,4,5-tetrahydrobenz[cd]indole-2-carboxylic acid methyl ester (54 mg, 0.148 mmol) and p-toluenesulfonic acid (3 mg) in toluene (1 mL) was refluxed for 1 h, diluted with ethyl acetate, washed with water and brine, dried over MgSO4, and concentrated to give 52 mg of the title compound (quant): 1H NMR (DMSO-d6) δ12.17 (bs, 1H), 11.60 (s, 1H), 7.17 (s, 1H), 6.84 (s, 1H), 3.88 (s, 3H), 3.77 (m, 1H), 2.94 (mt, 1H, J=13.9 Hz), 2.80 (md, 1H, J=17.2 Hz), 2.56 (dd, 1H, J=15.2, 4.3 Hz), 2.37 (dd, 1H, J=15.2, 10.6 Hz), 2.11 (md, 1H, J=12.5 Hz), 1.88 (m, H).
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][CH:29]=[CH:28][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[N:19]=[C:18](Cl)[CH:17]=[C:16]([NH:21][C:22]3[NH:23][N:24]=[C:25]([CH3:27])[CH:26]=3)[N:15]=2)=[CH:9][CH:8]=1)=[O:5].[NH:32]1[CH2:35][CH2:34][CH2:33]1.C(N(CC)C(C)C)(C)C>C(O)CCC>[N:32]1([C:18]2[CH:17]=[C:16]([NH:21][C:22]3[NH:23][N:24]=[C:25]([CH3:27])[CH:26]=3)[N:15]=[C:14]([S:13][C:10]3[CH:9]=[CH:8][C:7]([NH:6][C:4](=[O:5])[C:3]4[CH:28]=[CH:29][CH:30]=[CH:31][C:2]=4[Cl:1])=[CH:12][CH:11]=3)[N:19]=2)[CH2:35][CH2:34][CH2:33]1
Reactant: Cc1cc(Nc2cc(Cl)nc(Sc3ccc(NC(=O)c4ccccc4Cl)cc3)n2)[nH]n1
Reactant: C1CNC1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Nc2cc(N3CCC3)nc(Sc3ccc(NC(=O)c4ccccc4Cl)cc3)n2)[nH]n1
Temperature: 90 °C
Reaction time: 5 h
Yield: 56.3 %

Procedure:
A 500 mL round bottom flask was charged with 2-chloro-N-{4-[4-chloro-6-(5-methyl-2H-pyrazol-3-ylamino)-pyrimidin-2-ylsulfanyl]-phenyl}-benzamide (16.0 g, 34.0 mmol), azetidine (3.87 g, 68.0 mmol), N,N-diisopropylethylamine (13.0 mL, 74.7 mmol) and n-butanol (250 mL). The reaction mixture was stirred at 90° C. for 5 h. The reaction mixture was cooled and concentrated in vacuo. Diethyl ether (200 mL) was added and a light brown solid precipitated. The solution was filtered and the solid recrystallized from ethanol to give the pure product as a white solid (9.42 g, 52%) 1H NMR (DMSO): 2.04 (3H, s), 2.32 (2H, m), 3.87 (4H, m), 5.39 (1H, s), 5.66 (1H, br s), 7.48-7.59 (6H, m), 7.82 (2H, m), 9.87 (1H, s), 10.74 (1H, s), 11.68 (1H, s); MS (ES+): 492.
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6](Br)[F:7])(=O)[CH3:2].[CH2:9]1C[O:12][CH2:11][CH2:10]1.C(OCC(Br)F)(=[O:16])C.C1COCC1.C(OC(C)C)(C)C>O>[F:7][CH:6]([CH:11]([OH:12])[CH2:10][CH3:9])[C:5]([O:4][CH2:1][CH3:2])=[O:16]
Reactant: CC(=O)OCC(F)Br
Reactant: C1CCOC1
Solvent: CC(C)OC(C)C
Solvent: O
Product: CCOC(=O)C(F)C(O)CC
Reaction time: 0.33 h
Yield: 85 %

Procedure:
After a 500 mL reaction vessel which had been sufficiently dried inside by vacuum heating was replaced with dry nitrogen, and placed in an ice bath, 24.2 g (370 mmol/1.5 equivalent) of activated metal zinc and 300 mL of THF (dehydrated) were added into the reaction vessel. Thereto was added a bromofluoroethyl acetate/THF solution (46.91 g (253.6 mmol/1.0 equivalent) of bromofluoroethyl acetate and 80 mL of THF (dehydrated)) dropwise over 5 min. After the dropwise addition, the temperature of the mixture was elevated to the room temperature, followed by stirring for 20 min. Thereto was added a propionealdehyde/THF solution (17.76 g (305.8 mmol/1.2 equivalent) of propionealdehyde and 80 mL of THF (dehydrated)), and the mixture was stirred for 60 min at a room temperature. Thereafter, water and diisopropyl ether were added thereto, and two-layer separation was carried out. The organic layer thus obtained was washed with diluted hydrochloric acid and water, and the moisture was eliminated using magnesium sulfate, followed by filtration. Then diisopropyl ether was distilled off to give 35.4 g (yield: 85%) of ethyl 2-fluoro-3-hydroxy-pentanoate represented by the following formula.
Reaction SMILES: C(=O)([O-])O.[Na+].[CH2:6]([OH:14])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[C:15](OC=C)(=[O:17])[CH3:16].C(OCCCCCCCC)=C>C1(C)C=CC=CC=1>[C:15]([O:14][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])(=[O:17])[CH3:16]
Reactant: C=COC(C)=O
Reactant: CCCCCCCCO
Agent: C=COCCCCCCCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCCCCCCOC(C)=O
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a mixture of di-μ-chlorobis(1,5-cyclooctadiene)diiridium(I) [Ir(cod)Cl]2 (0.01 mmol) and sodium hydrogencarbonate (1.2 mmol) in toluene (1.0 ml), 1-octanol (130 mg, 1 mmol) and vinyl acetate (2 mmol) were added, followed by stirring at 100° C. in an atmosphere of argon gas for 2 hours. The reaction mixture was analyzed by gas chromatography to find that 1-octyl vinyl ether and octyl acetate were produced in yields of 93% and 2%, respectively, with a conversion from 1-octanol of 99%.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([O:9][CH3:10])=[CH:4][C:3]=1[CH2:11][NH2:12].C(N(CC)CC)C.Cl[C:21]([O:23][CH3:24])=[O:22]>C1COCC1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([O:9][CH3:10])=[CH:4][C:3]=1[CH2:11][NH:12][C:21](=[O:22])[O:23][CH3:24]
Reactant: COC(=O)Cl
Reactant: COc1cc(Cl)c(Cl)c(CN)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)NCc1cc(OC)cc(Cl)c1Cl
Temperature: 5 °C
Reaction time: 1 h
Yield: 95.4 %

Procedure:
A stirred solution of 54.0 grams (0.262 mole) of 2,3-dichloro-5-methoxy-phenylmethylamine and 27.0 grams (0.267 mole) of triethylamine in 1000 mL of THF was cooled below 5° C., and 24.8 grams (0.262 mole) of methyl chloroformate was added dropwise at a rate to maintain the reaction mixture temperature below 5° C. Upon completion of addition, the reaction mixture was stirred at about 5° C. for one hour, then it was allowed to warm to ambient temperature as it stirred for about 18 hours. After this time thin layer chromatographic (TLC) analysis of the reaction mixture indicated the reaction was complete. The reaction mixture was concentrated under reduced pressure to a residue, which was then shaken with ethyl acetate and water. The aqueous layer was washed with ethyl acetate, and the wash was combined with the original organic layer. The combination was then washed with one portion of water and one portion of an aqueous saturated sodium chloride solution. The organic layer was dried with sodium sulfate, filtered, and concentrated under reduced pressure, yielding 66.0 grams (95.3% yield) of the subject compound, mp 90°-91° C. (99% pure by gas chromatographic (GC) analysis). The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]3[CH:16]=2)=[C:4]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH:3]=1.[C:22](=O)([O-])[O-].[K+].[K+].CI>CS(C)=O>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]3[CH:16]=2)=[C:4]([N:17]([CH3:22])[S:18]([CH3:21])(=[O:20])=[O:19])[CH:3]=1
Reactant: CS(=O)(=O)Nc1cc(O)ccc1-c1cn2ccccc2n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CS(C)=O
Product: CN(c1cc(O)ccc1-c1cn2ccccc2n1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.1 g (3.6 mmol) of 2-(4-Hydroxy-2-methylsulphonamido-phenyl)-imidazo[1,2-a]pyridine are dissolved in 10 ml of dimethylsulphoxide, then 0.6 g (4.3 mmol) of potassium carbonate and 1.1 ml (18 mmol) of methyliodide are added. The mixture is stirred at ambient temperature for one hour. It is poured onto about 100 ml of ice water and the precipitate is suction filtered. It is then washed with water.