Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:25](O)[CH2:26][CH2:27][OH:28]>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]12[O:28][CH2:27][CH2:26][CH2:25][O:12]1
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Reactant: OCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: O=C1Nc2ccc(Cl)cc2C12OCCCO2
Temperature: 25 °C
Yield: 72.4 %

Procedure:
A mixture of 5-chloroisatin (5.00 g, 27.5 mmol), p-toluenesulfonic acid monohydrate (1.05 g, 5.5 mmol, 0.2 mole %) and 1,3 propanediol (6.04 mL, 83 mmol, 3 eq) in benzene (535 mL) was refluxed with a Dean Stark Trap for 7.5 hr. After cooling to room temperature the solution was decanted from the reaction mixture and concentrated The residue was washed with sat. aq. NaHCO3 (2×), brine (1×), dried over Na2SO4, filtered and concentrated. The crude product was purified on Biotage KP silica gel eluting with 70/30 Petroleum ether/EtOAc to give the title compound as a pale yellow solid (4.77 g, 72.5% ). A portion was dried at 42° C. in vacuo to give the analytically pure sample. Anal: Calc'd for C11H10ClNO3: C, 55.13; H, 4.21; N, 5.84. Found: C, 55.31; H, 4.34; N, 5.78. NMR (300 Mz, DMSO-d6): consistent. IR: consistent. MS: (ES−) m/z 238 [M−H]; one Cl pattern observed, consistent. m.p.: 184-185° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Cl[CH2:11][CH2:12][CH2:13]Br.[CH3:15][C@H:16]1[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]1>>[CH3:15][C@H:16]1[CH2:21][CH2:20][CH2:19][N:18]([CH2:11][CH2:12][CH2:13][O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH2:17]1
Reactant: ClCCCBr
Reactant: C[C@H]1CCCNC1
Reactant: O=Cc1ccc(O)cc1
Product: C[C@H]1CCCN(CCCOc2ccc(C=O)cc2)C1

Procedure:
This was produced according to the method of Reference Example 1-(4) but starting from 4-hydroxybenzaldehyde, 3-chloro-bromopropane and (3S)-3-methylpiperidine.
Reaction SMILES: [C:1]([Si:5]([CH3:18])([CH3:17])[N:6]1[C:10]2=[N:11][CH:12]=[C:13]([CH:15]=[O:16])[CH:14]=[C:9]2[CH:8]=[CH:7]1)([CH3:4])([CH3:3])[CH3:2].[O-:19]Cl=O.[Na+]>C(O)(C)(C)C.CC(=CC)C.O>[C:1]([Si:5]([CH3:18])([CH3:17])[N:6]1[C:10]2=[N:11][CH:12]=[C:13]([C:15]([OH:19])=[O:16])[CH:14]=[C:9]2[CH:8]=[CH:7]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)n1ccc2cc(C=O)cnc21
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: CC(C)(C)[Si](C)(C)n1ccc2cc(C(=O)O)cnc21
Yield: 16.4 %

Procedure:
To a stirred and cooled (0° C.) solution of aldehyde 16 (115 mg, 0.44 mmol) in tert-butanol (3.1 mL) and 2-methyl-2-butene (0.77 mL) was added a solution of NaClO2 (194 mg, 2.1 mmol) and NaH2PO4.H2O (244 mg, 1.8 mmol) in water (2.31 mL) dropwise. When 16 was consumed (TLC) the mixture was partitioned between AcOEt and water. The organic layer was washed with saturated brine (1×), dried (MgSO4), filtered and concentrated to afford acid 11 (20 mg, 16%) as an off-white solid. 1H NMR (400 MHz; CDCl3) δ 0.66 (s, 6H), 0.94 (s, 9H), 6.65 (s, 1H), 7.32 (s, 1H), 8.61 (s, 1H) and 9.03 (s, 1H).
Reaction SMILES: C1(/C=[CH:8]/[C:9]2[CH:14]=[N:13][C:12]3=[N:15][S:16][N:17]=[C:11]3[CH:10]=2)C=CC=CC=1.C[N+]1([O-])CC[O:22]CC1.O.I([O-])(=O)(=O)=O.[Na+]>[Os](=O)(=O)(=O)=O.O.CC(C)=O>[N:17]1[S:16][N:15]=[C:12]2[C:11]=1[CH:10]=[C:9]([CH:8]=[O:22])[CH:14]=[N:13]2
Reactant: C(=C/c1cnc2nsnc2c1)\c1ccccc1
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CC(C)=O
Product: O=Cc1cnc2nsnc2c1
Reaction time: 20 h

Procedure:
To 6-[(E)-2-phenylethenyl][1,2,5]thiadiazolo[3,4-b]pyridine (0.88 g, 3.68 mmol) was added acetone (30 ml), N-methyl-morpholine-N-oxide, 50 wt. % in water (1.525 ml, 7.35 mmol) and then osmium tetroxide in water (0.225 ml, 0.037 mmol). The reaction was then stirred for 20 hours. To the pale brown solution was added sodium periodate (3.15 g, 14.71 mmol) and stirring continued for 45 mins. The solvent was reduced by rotary evaporation and the remainder partitioned between chloroform and water. The aqueous was further extracted with chloroform and the combined organic extracts passed through a hydrophobic frit and concentrated to give brown/black solid (0.6 g). A portion of this material (0.575 g) was purified by chromatography on silica eluting with 20% EtOAc in cyclohexane to a pale yellow solid (160 mg).
Reaction SMILES: F[C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][CH:3]=1.[NH2:15][CH2:16][CH2:17][N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1>O>[N:18]1([CH2:17][CH2:16][NH:15][C:2]2[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][CH:3]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: NCCN1CCCC1
Reactant: CC(C)(C)OC(=O)c1ccc(F)cc1
Solvent: O
Product: CC(C)(C)OC(=O)c1ccc(NCCN2CCCC2)cc1
Temperature: 120 °C
Reaction time: 24 h
Yield: 51 %

Procedure:
A mixture of tert-butyl 4-fluorobenzoate (2.14 g) and 1-(2-aminoethyl)pyrrolidine (1 mL) is stirred at 120° C. for one day. After cooling, to the reaction mixture is added water and the mixture is extracted with ethyl acetate (×2). The extract is concentrated by centrifugal concentrator and the residue is purified by flash column chromatography on NH-silica gel (Solvent; n-hexane:ethyl acetate=8:1→4:1) to give tert-butyl 4-[[2-(1-pyrrolidinyl)ethyl]amino]benzoate (1.62 g, yield; 51%) as an oil. MS (APCI) m/z: 291 [M+H]+
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7](Cl)[CH:6]=[C:5]2[CH3:13].[CH3:14][NH:15][CH3:16]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:15]([CH3:16])[CH3:14])[CH:6]=[C:5]2[CH3:13]
Reactant: CNC
Reactant: Cc1cc(Cl)nc2ccc(Br)cc12
Solvent: CCO
Product: Cc1cc(N(C)C)nc2ccc(Br)cc12
Temperature: -78 °C
Yield: 134.4 %

Procedure:
A solution of 0.26 g (0.00101 mole) of 6-bromo-2-chloro-4-methylquinoline in 50 ml absolute ethanol was placed in a glass bomb liner, cooled to -78° C., and 7.19 g (0.159 mole) of dimethylamine bubbled into the cold ethanolic solution. The mixture was heated to 112° in a sealed autoclave for 3 hours. The solvent and excess dimethylamine were then removed under vacuum, to leave 0.36 g of residue, which was washed with 40 ml H2O to remove the (CH3)2NH.HCl. The product was then taken up in 40 ml absolute ethanol, treated with Norite A alkaline decolourising carbon and filtered through Celite followed by concentration and addition of 7 ml H2O to induce crystallisation after chilling, the product collected was a light yellow crystalline solid, 0.20 g (74.3%), m.p. 81.9°-84.1° C., and Rf 0.11 on silica with 1:1 CH2Cl2 :hexane.
Reaction SMILES: [CH3:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[CH:8]=[C:7]([F:13])[C:3]=1[C:4](O)=[O:5].[Cl-:14]>>[CH3:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[CH:8]=[C:7]([F:13])[C:3]=1[C:4]([Cl:14])=[O:5]
Reactant: Cc1c(F)c(F)cc(F)c1C(=O)O
Reactant: [Cl-]
Product: Cc1c(F)c(F)cc(F)c1C(=O)Cl

Procedure:
To 2-methyl-3,4,6-trifluorobenzoic acid (3.2 g) is added thiony chloride (7 ml) and the mixture is refluxed for hour. After concentrating, 2-methyl-3,4,6-trifluorobenzoyl chloride (3.3 g) is obtained.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=[O:7].CN1C[CH2:12][CH2:11][C:10]1=O.BrCCC.C(=O)([O-])[O-].[K+].[K+]>O>[CH2:10]([N:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=[O:7])[CH2:11][CH3:12]
Reactant: O=Cc1ncc[nH]1
Reactant: CN1CCCC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCBr
Solvent: O
Product: CCCn1ccnc1C=O
Temperature: 40 °C
Reaction time: 12 h

Procedure:
To 1H-imidazole-2-carboaldehyde (800 mg), N-methylpyrrolidone (10 mL) was added, followed by dissolution with heating. To this solution, 1-bromopropane (2.05 g) and potassium carbonate (1.15 g) were added. The reaction solution was stirred at 40° C. for 12 hours. To the reaction solution, water (10 mL) was added. The aqueous layer was extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine and then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (dichloromethane) to obtain the title compound (893 mg) having the following physical properties.
Reaction SMILES: [Br-].[CH2:2]([S:18][CH2:19][CH:20]([O:28][CH3:29])[CH2:21][N+:22]([CH3:27])([CH3:26])[CH2:23][CH2:24][OH:25])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[CH2:30](SCC(OCC)C[Br:50])CCCCCCCCCCCCCCC.CN(CCO)C>>[Br-:50].[CH2:2]([S:18][CH2:19][CH:20]([O:28][CH2:29][CH3:30])[CH2:21][N+:22]([CH3:26])([CH3:27])[CH2:23][CH2:24][OH:25])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCCCCCCCCCCSCC(C[N+](C)(C)CCO)OC
Reactant: CCCCCCCCCCCCCCCCSCC(CBr)OCC
Agent: CN(C)CCO
Agent: [Br-]
Product: CCCCCCCCCCCCCCCCSCC(C[N+](C)(C)CCO)OCC
Yield: 30 %

Procedure:
This product was prepared in an analogous manner to that of (±)-3-hexadecylthio-2-methoxy-N, N-dimethyl-N-β-hydroxyethyl-1-propyl ammonium bromide from 2.2 grams (0.005 mole) of (±)-1-hexadecylthio-2-ethoxy-3-bromopropane and 0.15 milliliter (0.006 mole) of N,N-dimethylaminoethanol to give 0.775 milligram (30%) of product, (mp 112°-113° Centigrade). 1H-NMR (CDCl3): delta, 0.87(t, 3H, terminal methyl), 1.2-1.6[m, 31H, (CH2)14, CH3 --CH2 --O], 2.58(m, 2H, S--CH2), 2.7-2.9(m, 2H, CH2 --S), 3.48[s, 6H, N(CH3)2 ], 3.9-4.3(m, 9H, CH, CH2 --N--CH2 --CH2 --OH, CH3 --CH2 --O). Anal. (C25H54NO2SBr) C,H,N.
Reaction SMILES: C([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[O:10][C:9]([C:18]2[N:23]=[CH:22][N:21]3[CH:24]=[CH:25][CH:26]=[C:20]3[CH:19]=2)=[CH:8]1)(C)(C)C.Cl.[Cl:28][CH2:29][CH2:30][CH2:31][N:32]([CH3:34])[CH3:33].Cl>C(O)(C)C>[CH3:33][N:32]([CH3:34])[CH2:31][CH2:30][CH2:29][O:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[O:10][C:9]([C:18]1[N:23]=[CH:22][N:21]3[CH:24]=[CH:25][CH:26]=[C:20]3[CH:19]=1)=[CH:8][C:7]2=[N:6][OH:5].[ClH:28].[CH3:33][N:32]([CH3:34])[CH2:31][CH2:30][CH2:29][O:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[O:10][C:9]([C:18]1[N:23]=[CH:22][N:21]3[CH:24]=[CH:25][CH:26]=[C:20]3[CH:19]=1)=[CH:8][C:7]2=[N:6][OH:5]
Reactant: CC(C)(C)ON=c1cc(-c2cc3cccn3cn2)oc2ccc(O)cc12
Reactant: CN(C)CCCCl
Agent: Cl
Solvent: CC(C)O
Product: CN(C)CCCOc1ccc2oc(-c3cc4cccn4cn3)cc(=NO)c2c1

Procedure:
6-(3-Dimethylamino-propoxy)-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one oxime was prepared in 22% overall yield using the procedure described in example 42A, starting from 6-hydroxy-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one O-tert-butyl oxime (example 81A) and (3-Chloro-propyl)-dimethyl-amine hydrochloride. The compound was treated with a 1.25 N solution of hydrogen chloride in isopropanol to yield 6-(3-Dimethylamino-propoxy)-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one oxime hydrochloride as an orange solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.[C:13]([C:17]1[S:21][C:20]([NH:22][C:23](=[O:29])[CH:24]([NH2:28])[CH2:25][CH2:26][CH3:27])=[N:19][N:18]=1)([CH3:16])([CH3:15])[CH3:14].CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C>C(Cl)Cl>[C:13]([C:17]1[S:21][C:20]([NH:22][C:23](=[O:29])[CH:24]([NH:28][C:10](=[O:12])[CH2:9][C:4]2[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=2)[CH2:25][CH2:26][CH3:27])=[N:19][N:18]=1)([CH3:15])([CH3:14])[CH3:16]
Reactant: CCCC(N)C(=O)Nc1nnc(C(C)(C)C)s1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1nnc(C(C)(C)C)s1
Temperature: 25 °C

Procedure:
A mixture of 3,5-di-fluoro-phenyl acetic acid (51.6 mg, 0.3 mmol), 2-amino-pentanoic acid (5-tert-butyl-[1,3,4]thiadiazol-2-yl)-amide (88 mg, 0.3 mmol), HBOT (43 mg, 0.315 mmol), EDC HCl (69 mg, 0.36 mmol.) and triethylamine (0.17 ml) in methylene chloride was stirred at room temperature until product formation or disappearance of starting material. The mixture was quenched with water and extracted with methylene chloride. The organic layer was separated, washed with dilute HCl, brine, dried over sodium sulfate and the solvent was removed at reduced pressure to provide the title compound as a cude oil. The oil was purified by Shimadzu HPLC to provide the title compound as a white solid (56 mg), LC-MS M+1=411.2, 1H NMR(CDCL3) 8.7 (d, 1H,NH), 6.73(m,2H), 6.6(m, 1H), 4.7(m, 1H), 3.5(Abq, 2H), 1.6-1.9(m,2H), 1.3-1.6(m,2H), 1.5(s,9H), 0.92(t,3H) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]([C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=2)O)=O)=[CH:4][CH:3]=1.[NH2:19][C:20]([NH2:22])=[S:21].O.C(O)C>C(O)CCCCC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:19][C:20](=[S:21])[NH:22][C:10]=2[C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Br)cc1)C(O)c1ccc(Br)cc1
Reactant: NC(N)=S
Solvent: O
Solvent: CCCCCCO
Solvent: CCO
Product: S=c1[nH]c(-c2ccc(Br)cc2)c(-c2ccc(Br)cc2)[nH]1

Procedure:
A mixture of 4,4'-dibromobenzoin (25 g, 0.068 mol) and thiourea (10.3 g, 0.14 mol) in hexanol (200 ml) was refluxed with azeotropic distillation of water for three hours. The solution was then cooled and ethanol (300 ml) was added. The mixture was further cooled and the small needles which formed were collected and washed with cold ethanol then ether and dried. Recrystallization of the product from ethyl acetate gave 4,5-bis-(4-bromophenyl)-1H-imidazole-2-thione, m.p. 288°.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:29][CH2:28][N:18]2[C:19]3[CH:20]=[C:21]([S:26][CH3:27])[CH:22]=[CH:23][C:24]=3[CH2:25][CH:17]2[CH2:16]1)=O)(C)(C)C.C(=O)([O-])O.[Na+].[C:35]([OH:42])(=[O:41])/[CH:36]=[CH:37]/[C:38]([OH:40])=[O:39]>ClCCl.CC(O)C>[C:35]([OH:42])(=[O:41])/[CH:36]=[CH:37]/[C:38]([OH:40])=[O:39].[CH3:27][S:26][C:21]1[CH:22]=[CH:23][C:24]2[CH2:25][CH:17]3[CH2:16][NH:15][CH2:29][CH2:28][N:18]3[C:19]=2[CH:20]=1
Reactant: CSc1ccc2c(c1)N1CCN(C(=O)OC(C)(C)C)CC1C2
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CC(C)O
Product: CSc1ccc2c(c1)N1CCNCC1C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
Trifluoroacetic acid (1 mL) was added to a stirred solution of 2-tert-butoxycarbonyl-7-(methylthio)-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole (70 mg, 0.21 mmol) in dichloromethane. (5 mL) at room temperature under Ar. The reaction was stirred at room temperature for 1 h then poured into saturated aqueous sodium hydrogen carbonate solution (50 mL) and extracted with dichloromethane (3×30 mL). The combined organic extracts, were washed with brine (1×30 mL), dried (magnesium sulfate), filtered and the solvent removed under vacuum to leave a crude oil. The oil was dissolved in 2-propanol (5 mL) and heated to reflux. Fumaric acid (1 eq) was added and the solution was cooled to room temperature. The emerging precipitate was filtered, washed with ether and dried to give the product as a white solid (40 mg, 54%). mp 196–198° C. Found: C, 56.50; H, 5.89; N, 8.15%. C12H16N2S. 1.1 C4H4O4 requires: C, 56.60; H, 5.91; N, 8.05%. IR νmax (Nujol)/cm−1 3595, 3188, 2925, 2854, 2457, 1696, 1585, 1485, 1486, 1461, 1402, 1377, 1345, 1317, 1279, 1230, 1179, 1154, 1129, 1066, 1058, 1005, 996, 972, 919, 987, 868, 835, 797, 722, 644, 606, 547 and 482: NMR δH (400 MHz; DMSO-d6) 6.99 (1H, d, J 7.5 Hz), 6.52 (2H, s), 6.47–6.51 (2H, m), 3.69–3.72 (1H, m), 3.50–3.62 (2H, m), 3.05–3.20 (3H, m), 2.91–3.02 (2H, m), 2.65–2.80 (2H, m), 2.43 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([CH2:24][CH2:25][NH:26][S:27]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH:37]=O)(=[O:29])=[O:28])=[C:5]2[CH2:39][CH2:40][CH2:41][C:42]1[CH:51]=[CH:50][C:45]([C:46]([O:48]C)=[O:47])=[CH:44][CH:43]=1.[NH:52]1[CH2:57][CH2:56][O:55][CH2:54][CH2:53]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([CH2:24][CH2:25][NH:26][S:27]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH2:37][N:52]1[CH2:57][CH2:56][O:55][CH2:54][CH2:53]1)(=[O:29])=[O:28])=[C:5]2[CH2:39][CH2:40][CH2:41][C:42]1[CH:51]=[CH:50][C:45]([C:46]([OH:48])=[O:47])=[CH:44][CH:43]=1
Reactant: COC(=O)c1ccc(CCCc2c(CCNS(=O)(=O)Cc3ccccc3C=O)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: O=C(O)c1ccc(CCCc2c(CCNS(=O)(=O)Cc3ccccc3CN3CCOCC3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Temperature: 25 °C
Yield: 65.2 %

Procedure:
To methyl 4-{3-[5-chloro-1-(diphenylmethyl)-2-(2-{[(2-formylbenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoate (Example 16, Step 5, 58 mg, 0.081 mmol) in DCE (2 mL) at 0° C. were added morpholine (0.0092 mL, 0.105 mmol) and NaBH(OAc)3 (27 mg, 0.13 mmol) and the reaction mixture was allowed to warm to rt overnight. The reaction was quenched with sat. NaHCO3, extracted with EtOAc, and dried over MgSO4. Purification by silica gel chromatography (35% to 50% EtOAc/hexanes) gave the desired product as a white solid (41 mg, 64%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH:4]([OH:18])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=1)=[O:6].[C:19]([N:23]=[C:24]=[O:25])([CH3:22])([CH3:21])[CH3:20].C(N(CC)CC)C>ClCCl>[Br:1][CH2:2][CH2:3][CH:4]([O:18][C:24](=[O:25])[NH:23][C:19]([CH3:22])([CH3:21])[CH3:20])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:16])[F:17])[CH:9]=1)=[O:6]
Reactant: CC(C)(C)N=C=O
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)C(O)CCBr
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=O)OC(CCBr)C(=O)Nc1cccc(C(F)(F)F)c1

Procedure:
By a procedure similar to that described in Step 1a above, 4-bromo-2-hydroxy-N(3-trifluoromethylphenyl)butanamide (0.52 g, prepared as described in Example 10, Step 1b above) was treated with t-butylisocyanate and triethylamine in dichloromethane to give the title compound (0.03 g, m.p. 107°-109° C.). NMR (CDCl3): δ 1.4(9H,s); 2.4(2H,m); 3.6(2H,t); 5.1(1H,bs); 5.3(1H,t); 7.3(2H,m); 7.6(1H,d); 7.8(1H,bs); 8.8(1H,bs). MS: M+ 424, 426. Under the extended time of this reaction, the major product was that of base-catalysed cyclisation (0.16 g, m.p. 114°-116° C.), identical to material described in Example 10, Step 3 above and Example 11, Step 2 below.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:20][NH:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]2[CH2:33][CH2:32][NH:31][CH2:30]2)[CH:24]=1>>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11]([N:31]4[CH2:32][CH2:33][CH:29]([C:25]5[CH:26]=[CH:27][CH:28]=[C:23]([CH2:22][NH:21][CH3:20])[CH:24]=5)[CH2:30]4)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: CNCc1cccc(C2CCNC2)c1
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Product: CNCc1cccc(C2CCN(c3cc4c(cc3F)c(=O)c(C(=O)O)cn4C3CC3)C2)c1
Yield: 91 %

Procedure:
Starting from 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (0.93 g, 3.5 mmol) and N-methyl-3-(3-pyrrolidinyl) benzenemethanamine, a procedure analogous to that given in Example 1 provided the title compound (1.38 g, 91%) as a white solid, mp 239°-240° C.
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:40])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[C:30]5[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=5)[NH:24][N:23]=4)[N:20]=3)[N:15]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2].[H-].[Na+].Br[CH2:44][CH2:45][O:46][CH:47]1[CH2:52][CH2:51][CH2:50][CH2:49][O:48]1>CN(C=O)C>[C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:40])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[C:30]5[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=5)[N:24]([CH2:44][CH2:45][O:46][CH:47]5[CH2:52][CH2:51][CH2:50][CH2:49][O:48]5)[N:23]=4)[N:20]=3)[N:15]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2]
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4cc(Cl)ccc34)nc12)C(=O)N1CC(C#N)C1
Reactant: BrCCOC1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CCOC4CCCCO4)c4cc(Cl)ccc34)nc12)C(=O)N1CC(C#N)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92.9 %

Procedure:
In a round-bottomed flask, 2-(6-chloro-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide (see Example 23, 120 mg, 0.21 mmol) was dissolved in DMF (1.3 ml). The reaction mixture was cooled to 0° C. and sodium hydride (60% dispersion in mineral oil, 10 mg, 0.25 mmol) was added. The reaction mixture was stirred at 0° C. for 30 min then 2-(2-bromoethoxy)tetrahydro-2H-pyran (47 μl, 0.31 mmol) was added. The reaction mixture was stirred at 0° C. for 1 h and then at room temperature for 4 h. The reaction mixture was quenched with water and extracted with ethyl acetate (2×). The combined organic layers were washed with water, sat LiCl, and brine then dried over MgSO4 and concentrated. The residue was chromatographed over silica gel with 50% to 100% EtOAc/heptane to afford 138 mg (94%) of 2-{6-chloro-1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-indazol-3-yl}-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide as a viscous yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[Cl:7].[OH-].[K+].[Br:10][CH2:11][CH2:12][CH2:13][CH3:14].[K+].[Br-].Br[CH2:18][CH2:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=1>C(#N)C>[Br-:10].[CH2:11]([N+:3]1[C:2]([Cl:1])=[C:6]([Cl:7])[N:5]([C:20]2([CH2:19][CH3:18])[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:21]2)[CH:4]=1)[CH2:12][CH2:13][CH3:14]
Reactant: CCCCBr
Reactant: Clc1nc[nH]c1Cl
Reactant: BrCCc1ccc2ccccc2c1
Agent: [Br-]
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: CCCC[n+]1cn(C2(CC)C=Cc3ccccc3C2)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4,5-Dichloroimidazole (1.23 g, 9 mmol) will be dissolved into acetonitrile. Potassium hydroxide (0.61 g, 9.9 mmol) will be added and the mixture will be allowed to stir for 0.5 h. 1-bromobutane (9 mmol) will be added and the solution will be allowed to reflux overnight. The solution will be filtered hot to remove a white precipitate (presumed to be KBr) and 2-(2-bromoethyl)naphthalene (9 mmol) will be added and the mixture will be returned to reflux overnight. The mixture will be allowed to cool to room temperature, and the volatiles will be removed en vacuo resulting in the product.