Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[N:10]=[C:11]([C:15]([O:17]C)=[O:16])[N:12]([CH3:14])[CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.O.O>[C:1]([O:5][C:6]([NH:8][C:9]1[N:10]=[C:11]([C:15]([OH:17])=[O:16])[N:12]([CH3:14])[CH:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1nc(NC(=O)OC(C)(C)C)cn1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cn1cc(NC(=O)OC(C)(C)C)nc1C(=O)O
Reaction time: 8 h
Yield: 81.5 %

Procedure:
Methyl 4-(tert-butoxycarbonylamino)-1-methyl-1H-imidazole-2-carboxylate (5.0 g, 19.59 mmol) in 120 ml of 1:1 THF/H2O was added 8 g of NaOH in 30 ml of water. The mixture was stirred overnight, concentrated, diluted with water, extracted with EtAc/Hexane (1:1). The aqueous solution was adjusted to pH 4.0 with 20% H3PO4 and extracted with EtAc (4×60 ml). The organic solutions were combined, dried over MgSO4, filtered, evaporated and crystallized with ethanol/EtAc/Hexane to afford 3.85 g (81%) of the title product. 1H NMR (DMSO) 9.32 (s, 1H), 7.29 (s, 1H), 3.57 (s, 3H), 1.42 (s, 9H); 13C NMR 172.45, 159.78, 136.93, 135.44, 132.85, 79.50, 35.57, 28.07; MS m/z− 240.8 (M−H).
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:10])=[C:4]([CH:8]=[O:9])[CH:5]=[N:6][CH:7]=1.[CH3:11][Mg]Br.CCOCC>C1COCC1>[Br:1][C:2]1[C:3]([Cl:10])=[C:4]([CH:8]([OH:9])[CH3:11])[CH:5]=[N:6][CH:7]=1
Reactant: O=Cc1cncc(Br)c1Cl
Reactant: C[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(O)c1cncc(Br)c1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a round bottom flask is added 5-bromo-4-chloro-pyridine-3-carbaldehyde (490 mg, 2.22 mmol) in 10 ml of THF at 0° C., followed by the addition of methylmagnesium bromide, 3M in ether (0.89 ml, 2.67 mmol). The reaction mixture is stirred at room temperature for 1 hour. The reaction mixture is concentrated. The residue is diluted with EtOAc/saturated NH4Cl. The organic layer is separated, washed with water, brine, dried over anhydrous Na2SO4, filtered and concentrated to give the crude product. Purification by the flash column chromatography affords 287 mg of 1-(5-bromo-4-chloro-pyridin-3-yl)-ethanol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10](B3OC(C)(C)C(C)(C)O3)=[CH:9][N:8]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:5]2=[N:6][CH:7]=1.Br[C:29]1[CH:30]=[C:31]([NH:35][C@H:36]([CH:45]([CH3:47])[CH3:46])[C:37]([NH:39][CH2:40][C:41]([F:44])([F:43])[F:42])=[O:38])[CH:32]=[N:33][CH:34]=1.C([O-])([O-])=O.[Na+].[Na+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:29]3[CH:30]=[C:31]([NH:35][CH:36]([CH:45]([CH3:47])[CH3:46])[C:37]([NH:39][CH2:40][C:41]([F:44])([F:43])[F:42])=[O:38])[CH:32]=[N:33][CH:34]=3)=[CH:9][N:8]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:25])([CH3:26])[CH3:27])[C:5]2=[N:6][CH:7]=1
Reactant: CC1(C)OB(c2cn(COCC[Si](C)(C)C)c3ncc(Cl)cc23)OC1(C)C
Reactant: CC(C)[C@@H](Nc1cncc(Br)c1)C(=O)NCC(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(C)C(Nc1cncc(-c2cn(COCC[Si](C)(C)C)c3ncc(Cl)cc23)c1)C(=O)NCC(F)(F)F
Temperature: 100 °C
Yield: 73.8 %

Procedure:
To a nitrogen gas purged mixture of 5-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine (231 mg, 0.565 mmol), (R)-2-(5-bromopyridin-3-ylamino)-3-methyl-N-(2,2,2-trifluoroethyl)butanamide (200 mg, 0.565 mmol), and Na2CO3 (847 μl, 1.694 mmol) in DME (3765 μl) was added Tetrakis (131 mg, 0.113 mmol). The reaction mixture was heated at 100° C. in a sealed microwave vessel for 1 h. Water (10 mL) was added and the mixture was extracted with ethyl acetate (2×20 mL). The combined organic extracts were dried with sodium sulfate, and concentrated under reduced pressure. Purification of the residue on silica (0-5% methanol/ethyl acetate, 25 gm silica) to give 232 mg foam, (2-1a).
Reaction SMILES: C([O:5][C:6](=[O:22])[CH:7]([CH3:21])[N:8]([C:12](=[O:20])[CH:13]([CH3:19])[CH2:14][S:15][C:16](=[O:18])[CH3:17])[CH:9]1[CH2:11][CH2:10]1)(C)(C)C>C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>[C:16]([S:15][CH2:14][CH:13]([CH3:19])[C:12]([N:8]([CH:9]1[CH2:10][CH2:11]1)[CH:7]([C:6]([OH:22])=[O:5])[CH3:21])=[O:20])(=[O:18])[CH3:17]
Reactant: CC(=O)SCC(C)C(=O)N(C1CC1)C(C)C(=O)OC(C)(C)C
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)SCC(C)C(=O)N(C1CC1)C(C)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.2 %

Procedure:
Crude N-(3-acetylthio-2-methylpropanoyl)-N-cyclopropyl-(dl)-alanine tert-butyl ester (60.2 g) was dissolved in a mixture of anisole (54 ml) and trifluoroacetic acid (96 ml). The resulting solution was stirred at room temperature for one hour. Trifluoroacetic acid was removed in vacuo and the residue was distributed between ethyl acetate and saturated sodium bicarbonate. The aqueous bicarbonate phase was separated and washed twice with ethyl acetate and then acidified to pH 4-5 with concentrated hydrocloric acid. The precipitated product was extracted into chloroform and washed twice with water. The organic phase was dried over magnesium sulfate, filtered and evaporated to give the crude acid as a thick yellow oil (22.9 g). The crude product was purified by HPLC, eluting with ethyl acetate/n-hexane/acetic acid (40:60:1), to give pure product as initially a pale yellow oil (9.6 g). The product was crystallized from ether/n-hexane to give colorless crystals, m.p. 83°-85° C.
Reaction SMILES: [CH:1]1(Br)[CH2:4][CH2:3][CH2:2]1.[CH3:6][O:7][C:8]1[C:9]([OH:23])=[C:10]([C:15]([N+:20]([O-:22])=[O:21])=[CH:16][C:17]=1[O:18][CH3:19])[C:11]([O:13][CH3:14])=[O:12].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[CH:1]1([O:23][C:9]2[C:8]([O:7][CH3:6])=[C:17]([O:18][CH3:19])[CH:16]=[C:15]([N+:20]([O-:22])=[O:21])[C:10]=2[C:11]([O:13][CH3:14])=[O:12])[CH2:4][CH2:3][CH2:2]1
Reactant: BrC1CCC1
Reactant: COC(=O)c1c([N+](=O)[O-])cc(OC)c(OC)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1c([N+](=O)[O-])cc(OC)c(OC)c1OC1CCC1
Temperature: 100 °C
Reaction time: 4 h
Yield: 42.1 %

Procedure:
Cyclobutyl bromide (0.44 ml, 0.0047 mol) was added to a suspension of methyl 3,4-dimethoxy-2-hydroxy-6-nitrobenzoate (1 g, 0.0039 mol) and potassium carbonate (1.2 g, 0.0086 mol) in dimethylformamide (10 ml) and the reaction stirred at 100° C. for 4 hours. On cooling, aqueous sodium carbonate solution was added and the mixture extracted with ethyl acetate (2×40 ml). The combined organic extracts were washed with water, dried (MgSO4), filtered and evaporated under reduced pressure. The crude product was purified on silica gel eluting with diethyl ether to give the subtitle compound as a colourless oil (511 mg, 42%). Rf 0.89 (diethyl ether). MS m/z 312 (MH)+. 1H-NMR (CDCl3): Γ=1.48 (1H, m), 1.76(1H, m), 2.27 (4H, m), 2.94(9H, m), 4.70(1H, m), 7.51 (1H, s).
Reaction SMILES: [C@@H:1]1([N:10]2[CH:18]=[N:17][C:16]3[C:11]2=[N:12][CH:13]=[N:14][C:15]=3[NH2:19])[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@@H:2]1[OH:3].[C:20](Cl)(=[O:22])[CH3:21]>CN(C)C=O.N1C=CC=CC=1>[C:20]([O:9][CH2:8][C@H:6]1[O:7][C@@H:1]([N:10]2[CH:18]=[N:17][C:16]3[C:11]2=[N:12][CH:13]=[N:14][C:15]=3[NH2:19])[C@@H:2]([OH:3])[C@@H:4]1[OH:5])(=[O:22])[CH3:21]
Reactant: CC(=O)Cl
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@@H](O)[C@@H]1O

Procedure:
To a stirred mixture of 2.67 g. of 9-(β-D-arabinofuranosyl)adenine and 100 ml. of 1:1 dimethylformamide-pyridine is added 0.79 g. of acetyl chloride at 25° C. The mixture is stirred, while being protected from moisture, for 1.5 hours, then treated with 50 g. of crushed ice and evaporated at reduced pressure. The residue is added to a 3× 40 cm. column of dry silica gel and the column is eluted sequentially with 500-ml. portions of 5, 10, 15 and 20% (v/v) methanol in chloroform. Two fractions of eluate (the 15 and 20% methanol in chloroform eluates) are combined and evaporated at reduced pressure to give the desired product 9-(5-O-acetyl-β-D-arabinofuranosyl)adenine; m.p. 197.5°-198.5° C. after crystallization from ethanol, [α]D23 = +23.6° (c = 1% in methanol), λmaxCH3OH = 258 nm (ε = 15,000), water solubility: 9.9 mg./ml.
Reaction SMILES: [CH2:1]([C:5]1([CH2:68][CH2:69][CH2:70][CH3:71])[C:17]2[CH:16]=[C:15]([N:18]([C:47]3[CH:59]=[CH:58][C:57]4[C:56]5[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=5)[C:50]([CH2:64][CH2:65][CH2:66][CH3:67])([CH2:60][CH2:61][CH2:62][CH3:63])[C:49]=4[CH:48]=3)[C:19]3[CH:31]=[C:30]4[C:22]([C:23]5[CH:24]=[CH:25][C:26]([C:40]6[S:44][C:43]([CH:45]=O)=[CH:42][CH:41]=6)=[CH:27][C:28]=5[C:29]4([CH2:36][CH2:37][CH2:38][CH3:39])[CH2:32][CH2:33][CH2:34][CH3:35])=[CH:21][CH:20]=3)[CH:14]=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:2][CH2:3][CH3:4].[C:72]([CH2:74][C:75]([OH:77])=[O:76])#[N:73]>C(#N)C.N1CCCCC1>[CH2:1]([C:5]1([CH2:68][CH2:69][CH2:70][CH3:71])[C:17]2[CH:16]=[C:15]([N:18]([C:47]3[CH:59]=[CH:58][C:57]4[C:56]5[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=5)[C:50]([CH2:60][CH2:61][CH2:62][CH3:63])([CH2:64][CH2:65][CH2:66][CH3:67])[C:49]=4[CH:48]=3)[C:19]3[CH:31]=[C:30]4[C:22]([C:23]5[CH:24]=[CH:25][C:26]([C:40]6[S:44][C:43]([CH:45]=[C:74]([C:72]#[N:73])[C:75]([OH:77])=[O:76])=[CH:42][CH:41]=6)=[CH:27][C:28]=5[C:29]4([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:36][CH2:37][CH2:38][CH3:39])=[CH:21][CH:20]=3)[CH:14]=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1(CCCC)c2ccccc2-c2ccc(N(c3ccc4c(c3)C(CCCC)(CCCC)c3ccccc3-4)c3ccc4c(c3)C(CCCC)(CCCC)c3cc(-c5ccc(C=O)s5)ccc3-4)cc21
Reactant: N#CCC(=O)O
Solvent: CC#N
Solvent: C1CCNCC1
Product: CCCCC1(CCCC)c2ccccc2-c2ccc(N(c3ccc4c(c3)C(CCCC)(CCCC)c3ccccc3-4)c3ccc4c(c3)C(CCCC)(CCCC)c3cc(-c5ccc(C=C(C#N)C(=O)O)s5)ccc3-4)cc21

Procedure:
As shown in Scheme 3, 7-bromo-9H-fluoren-2-ylamine is reacted with 1-iodobutane to form 7-bromo-9,9-dibutyl-9H-fluoren-2-ylamine (31); and 2-Iodo-9H-fluorene is reacted with 1-iodobutane to form 9,9-dibutyl-2-iodo-9H-fluorene (32). Then, 7-bromo-9,9-dibutyl-9H-fluoren-2-ylamine (31) is reacted with 9,9-dibutyl-2-iodo-9H-fluorene (32) by Ullman coupling reaction to obtain (7-bromo-9,9-dibutyl-9H-fluoren-2-yl)-bis-(9,9-dibutyl-9H-fluoren-2-yl)amine (33). Next, (7-bromo-9,9-dibutyl-9H-fluoren-2-yl)-bis-(9,9-dibutyl-9H-fluoren-2-yl)amine (33) is reacted with 5-formyl-2-thiopheneboronic acid by Suzuki coupling reaction to obtain 5-{7-[bis-(9,9-dibutyl-9H-fluoren-2-yl)amino]-9,9-dibutyl-9H-fluoren-2-yl}-thiophene-2-carbaldehyde (34a). Finally, in acetonitrile, 5-{7-[bis-(9,9-dibutyl-9H-fluoren-2-yl)amino]-9,9-dibutyl-9H-fluoren-2-yl}-thiophene-2-carbaldehyde (34a) is reacted with cyanoacetic acid by using piperidine as a catalyst, to obtain 3-(5-{7-[bis-(9,9-dibutyl-9H-fluoren-2-yl)amino]-9,9-dibutyl-9H-fluoren-2-yl}-thiophen-2-yl)-2-cyano-acrylic acid (35a).
Reaction SMILES: [C:1]([NH2:4])#[C:2][CH3:3].[C:5](Cl)(=[O:14])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]>C(N(CC)CC)C>[C:1]([NH:4][C:5](=[O:14])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])#[C:2][CH3:3]
Reactant: CCCCCCCCC(=O)Cl
Reactant: CC#CN
Solvent: CCN(CC)CC
Product: CC#CNC(=O)CCCCCCCC
Yield: 62 %

Procedure:
Propynylamine (10.4 ml, 151.2 mmol) was mixed with 150 ml of triethylamine in a round bottom flask immersed in a cold water bath, and vigorously stirred while nonanoyl chloride (27.0 ml, 149.75 retool) was added in portions from a dropping funnel over a 30 minute period. Additional triethylamine (100 ml) was added to facilitate stirring. At the end of the addition, the water bath was removed and the reaction was stirred for 30 minutes, then filtered. The filtrate was stripped down to a yellow solid. The solid was partitioned between ether and aqueous NaOH, requiring a considerable quantity of ether to dissolve. The combined ether extracts were stripped and recrystallized from heptane to give product as a white crystalline solid, 18.12 g, 92.8 mmol, 62% yield; top. 78°-79.5° C.; 1H NMR (CDCl3) ∂0.88 (t, J=6.0 Hz, 3 H), 1.28 (m, 10 H), 1.63 (m, 2 H), 2.19 (t, J= 7.6 Hz, 2 H), 2.22 (t, J=2.7 Hz, 1 H), 4.06 (dd, J=5.2, 2.6 Hz), 5.62 (br s, 1 H); EI mass spectrum m/z 196 (M+H)+.
Reaction SMILES: Br[C:2]1[N:3]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[C:4]2[C:9]([N:10]=1)=[C:8]([NH2:11])[N:7]=[C:6]([O:12][CH2:13][CH:14]([CH3:17])[CH2:15][CH3:16])[N:5]=2.[CH3:24][O-:25].[Na+]>CO>[CH3:17][CH:14]([CH2:15][CH3:16])[CH2:13][O:12][C:6]1[N:5]=[C:4]2[C:9]([N:10]=[C:2]([O:25][CH3:24])[N:3]2[CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)=[C:8]([NH2:11])[N:7]=1
Reactant: CCC(C)COc1nc(N)c2nc(Br)n(C3CCCCO3)c2n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCC(C)COc1nc(N)c2nc(OC)n(C3CCCCO3)c2n1

Procedure:
To a solution of 8-bromo-2-[(2-methylbutyl)oxy]-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (284 mg) in dry MeOH (2.54 mL) was added sodium methoxide solution (0.416 mL, 30% wt. MeOH) and the mixture was stirred at reflux for 1 h. The reaction was allowed to cool and was concentrated in vacuo. The resulting residue was dissolved in EtOAc (15 mL) and was poured into saturated ammonium chloride solution (15 mL). The organics were separated, dried over MgSO4, filtered and concentrated in vacuo to give the title compound as an orange foam (199 mg).
Reaction SMILES: Br[C:2]1[C:3]([C:14]([F:17])([F:16])[F:15])=[N:4][N:5]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][O:9]2)[C:6]=1[CH3:7].[Li]CCCC.CN([CH:26]=[O:27])C>C1COCC1>[CH3:7][C:6]1[N:5]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][O:9]2)[N:4]=[C:3]([C:14]([F:17])([F:16])[F:15])[C:2]=1[CH:26]=[O:27]
Reactant: Cc1c(Br)c(C(F)(F)F)nn1C1CCCCO1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1c(C=O)c(C(F)(F)F)nn1C1CCCCO1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A solution of 4-bromo-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-3-(trifluoromethyl)-1H-pyrazole (1.17 g, 3.74 mmol) in THF (13 mL) was cooled to −78° C., then n-BuLi (1.6 M in hexane, 3.7 mL, 6.0 mmol) was added dropwise. The reaction was held at −78° C. for 10 minutes, then DMF (580 μL, 7.5 mmol) was added and the reaction was stirred at −78° C. for 1.5 h. The reaction was quenched at −78° C. by addition of sat'd NH4Cl and ether, the phases were separated and the aqueous phase was washed with ether. The combined organic phase was washed with water, then sat'd NaCl, dried over MgSO4 and reduced to dryness in vacuo to give the crude product, which was used without further purification (1.04 g). 1H NMR (400 MHz, CDCl3): δ 10.0 (s, 1H), 5.41 (m, 1H), 4.00 (m, 1H), 3.66 (m, 1H), 2.68 (s, 3H), 2.41 (m, 1H), 2.17 (m, 1H), 2.00 (m, 1H), 1.69 (m, 3H).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]2[CH:10]=[C:11]([C:13](=[O:18])[CH2:14][CH2:15][CH2:16]Cl)[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2].Cl.[F:20][C:21]1[CH:35]=[CH:34][C:24]2[C:25]([CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[N:26][O:27][C:23]=2[CH:22]=1>>[C:1]([N:4]1[CH2:9][CH2:8][C:7]2[CH:10]=[C:11]([C:13](=[O:18])[CH2:14][CH2:15][CH2:16][N:31]3[CH2:30][CH2:29][CH:28]([C:25]4[C:24]5[CH:34]=[CH:35][C:21]([F:20])=[CH:22][C:23]=5[O:27][N:26]=4)[CH2:33][CH2:32]3)[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: CC(=O)N1CCc2cc(C(=O)CCCCl)sc2C1
Agent: Cl
Product: CC(=O)N1CCc2cc(C(=O)CCCN3CCC(c4noc5cc(F)ccc45)CC3)sc2C1
Yield: 36 %

Procedure:
The reaction and procedure were conducted in a similar manner as in Example 24 using 2.2 g of 6-acetyl-2-(4-chlorobutyryl)-4,5,6,7-tetrahydrothieno-[2,3-c]pyridine and 2.0 g of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine hydrochloride to give 1.3 g of 6-acetyl-2-(4-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)butyryl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine as white crystals, m.p. 145°-147° C.
Reaction SMILES: [NH2:1][C:2]1[C:6]([NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:13]=2)=[N:5]S(=O)[N:3]=1.[ClH:25]>CO>[ClH:25].[ClH:25].[ClH:25].[N:19]1([CH2:18][C:14]2[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=2)[O:11][CH2:10][CH2:9][CH2:8][NH:7][C:6](=[NH:5])[C:2](=[NH:1])[NH2:3])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: NC1=NS(=O)N=C1NCCCOc1cccc(CN2CCCC2)c1
Agent: Cl
Solvent: CO
Product: N=C(N)C(=N)NCCCOc1cccc(CN2CCCC2)c1

Procedure:
A suspension of 3-amino-4-[3-(3-pyrrolidinomethylphenoxy)propylamino]-1,2,5-thiadiazole 1-oxide (13.4 g; 38.3 mmoles) [prepared according to published United Kingdom patent application No. 2,067,987] in 350 mL of methanol was treated with 25.5 mL of concentrated HCl. The resultant solution was stirred for 3 hours at ambient temperature. Concentration of the solution followed by azeotropic removal of water with absolute ethanol gave the product. The crystalline residue was triturated with 150 mL of absolute ethanol, filtered and dried to give 10.8 g of the title compound, m.p. 195°-203° C. (dec.).
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][N+:16]([O-:18])=O)=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.C[O-].[Li+].C(Cl)[Cl:25]>O1CCCC1.[Ti](Cl)(Cl)(Cl)Cl>[CH2:1]([C:8]1[N:9]=[CH:10][C:11]([CH2:14][C:15]([Cl:25])=[N:16][OH:18])=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])CCc1ccc(Cc2ccccc2)nc1
Reactant: ClCCl
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: C[O-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: ON=C(Cl)Cc1ccc(Cc2ccccc2)nc1
Temperature: 0 °C
Yield: 63 %

Procedure:
To 2-benzyl-5-(2-nitro-ethyl)-pyridine (260 mg, 1.1 mmol) described in Manufacturing Example 210-1-6 and methanol (5 mL) was added lithium methoxide (81 mg, 2.1 mmol), which was concentrated under a reduced pressure. Titanium(IV) tetrachloride (0.38 mL, 3.4 mmol) was added dropwise at −76° C. to a suspension of the residue in methylene chloride (5 mL) and tetrahydrofuran (2.5 mL), which was stirred for 20 minutes at room temperature. This reaction solution was added to ice water and extracted with ethyl acetate. The aqueous layer was extracted with ethyl acetate again (four times). The organic layers were combined, washed with aqueous sodium chloride (one time), dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and tetrahydrofuran was added to the residue. The insolubles thus produced were filtered out. The filtrate was concentrated under a reduced pressure to obtain the title compound (180 mg, 63%).
Reaction SMILES: [OH-].[K+].[CH:3]1([CH:8]([NH:14][C:15]([O:17][CH3:18])=[O:16])[C:9]([O:11]CC)=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4]1>O.C(O)C>[CH:3]1([CH:8]([NH:14][C:15]([O:17][CH3:18])=[O:16])[C:9]([OH:11])=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: CCOC(=O)C(NC(=O)OC)C1CCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COC(=O)NC(C(=O)O)C1CCCC1
Yield: 89.1 %

Procedure:
KOH (3.87 g, 69.0 mmol) in water (50 mL) was added to ethyl 2-cyclopentyl-2-(methoxycarbonylamino)acetate (Compound I2.1) (7.6 g, 33.2 mmol) in ethanol (20 mL). The resultant mixture was stirred at rt for 5 h. Part of the solvent was removed under reduce pressure. The remaining mixture was extracted with Et2O (2×50 mL). The pH of the water layer was acidified by additions of HCl (1N, 20 mL) and the resultant mixture was extracted with DCM (3×50 mL), dried (MgSO4) and concentrated under reduce pressure. The residue was purified via Biotage (gradient: 10-80% of DCM/MeOH/HOAc (1: 0.05: 0.01) in DCM, KP-SIL 340 g column), KP-SIL 340 g column) to give the title product (5.95 g, 85%). 1H NMR (600 MHz, CDCl3) 1.26-1.48, 1.49-1.68, 1.68-1.85, 2.28, 3.69, 4.31, 5.12. Total no of protons: 14.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[C:11]([C:15]1[CH:23]=[C:22]2[C:18]([CH:19]=[CH:20][NH:21]2)=[CH:17][CH:16]=1)([O:13][CH3:14])=[O:12].[CH3:24][S:25](Cl)(=[O:27])=[O:26].O>C1COCC1>[CH3:24][S:25]([N:21]1[C:22]2[C:18](=[CH:17][CH:16]=[C:15]([C:11]([O:13][CH3:14])=[O:12])[CH:23]=2)[CH:19]=[CH:20]1)(=[O:27])=[O:26]
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Reactant: CS(=O)(=O)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc2ccn(S(C)(=O)=O)c2c1
Reaction time: 0.5 h

Procedure:
A solution of NaN(TMS)2 (1 M) in THF (11 mmol, 11 ml) was added dropwise to a -78° C solution of 6-carbomethoxyindole (876 mg, 5 mmol, prepared according to the procedure of Batcho, et al., Org. Synth. Coll. 7:34) in dry THF (10 ml). After stirring for 30 min, MeSO2Cl (1.47 mL) (Me=CH3) was added. The mixture was allowed to stir overnight then poured onto 100 ml of water. The mixture was extracted with CH2Cl2 (2×75 ml). The extracts were washed with brine, dried (Na2SO4), and the solvent was removed by rotary evaporation to give a light brown solid. The solid was purified by flash column chromatography (silica gel, 20% ethyl acetate/hexane) to give 510 mg of N-methanesulfonyl-6-carbomethoxyindole.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)([CH3:3])[CH3:2].Cl[C:11]1[N:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][N:12]=1>C(Cl)Cl.O>[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:11]2[N:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][N:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCNCC1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1
Solvent: O
Solvent: ClCCl
Product: CC(C)N1CCN(c2ncc([N+](=O)[O-])cn2)CC1
Temperature: 5 °C
Reaction time: 0.33 h
Yield: 89.1 %

Procedure:
1-Isopropylpiperazine (1.8 mL, 12.7 mmol, 2 equiv) was added to a cold (5° C.) solution of 2-chloro-5-nitropyrimidine (1 g, 6.3 mmol,) in DCM (5 mL). The reaction mixture was stirred for 20 min at 5° C. and then diluted with DCM and H2O. The aqueous layer was separated and extracted with DCM. The organic phase was washed with brine, dried (Na2SO4), filtered and concentrated to provide 1.41 g of the title compound as a beige solid: ESI-MS: 252.2 [M+H]+; tR=1.89 min.
Reaction SMILES: [CH3:1][C:2]1[C:14]2[N:13]3[C:8]([CH2:9][CH2:10][CH2:11][CH2:12]3)=[CH:7][C:6]=2[C:5](=O)[NH:4][N:3]=1.O=P(Cl)(Cl)[Cl:18].CO.[OH-].[Na+]>C(Cl)Cl>[Cl:18][C:5]1[C:6]2[CH:7]=[C:8]3[N:13]([C:14]=2[C:2]([CH3:1])=[N:3][N:4]=1)[CH2:12][CH2:11][CH2:10][CH2:9]3
Reactant: Cc1n[nH]c(=O)c2cc3n(c12)CCCC3
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: Cc1nnc(Cl)c2cc3n(c12)CCCC3
Yield: 92 %

Procedure:
Compound XI (3.00 g, 15 mmol) was heated under reflux with excess POCl3 (25 mL) until no starting material remained (TLC, silic gel, 5% methanol in methylene chloride), then poured over ice, made basic with aqueous sodium hydroxide and the aqueous phase extracted with methylene chloride to isolate the product. The organic phase was dried (MgSO4), filtered, and evaporated to give a residue which was purified by flash column chromatography (silica gel, 5% methanol in methylene chloride) to give 1-chloro-4-methyl-6,7,8,9-tetrahydropyridazino[4,5-b]indolizine XII (3.00 g, 92%)