Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:10]([CH:13]1[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][C:16](=[O:24])[CH2:15][CH2:14]1)(=[O:12])=[O:11].[CH2:25](O)[CH2:26][CH2:27][OH:28].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:10]([CH:13]1[CH2:14][CH2:15][C:16]2([O:28][CH2:27][CH2:26][CH2:25][O:24]2)[CH:17]=[C:18]1[C:19]([O:21][CH2:22][CH3:23])=[O:20])(=[O:12])=[O:11]
Reactant: CCOC(=O)C1=CC(=O)CCC1S(=O)(=O)Nc1ccc(F)cc1Cl
Reactant: OCCCO
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C1=CC2(CCC1S(=O)(=O)Nc1ccc(F)cc1Cl)OCCCO2
Temperature: 25 °C
Yield: 51.2 %

Procedure:
100 mg (0.27 mmol) of ethyl 6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-3-oxo-1-cyclohexene-1-carboxylate obtained in Example 7 was dissolved in 2 ml of toluene, and 0.04 ml (0.54 mmol) of propane-1,3-diol and 68 mg (0.27 mmol) of pyridinium p-toluenesulfonate were added thereto, followed by heating under reflux for 1 hour. After the reaction solution was cooled to room temperature, a saturated aqueous sodium hydrogencarbonate solution was added and extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; hexane:ethyl acetate=2:1), and the resulting solid was further washed with hexane to give 60 mg of the title compound as a white powder (yield: 51%).
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[C:16]2[C:11](=[N:12][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:14][CH:15]=2)[C@H:10]([N:21]([CH2:28][C:29]2[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[C:31]([C:39]([F:42])([F:41])[F:40])[CH:30]=2)[C:22](=O)[CH2:23][C:24](=O)[CH3:25])[CH2:9][C@@H:8]1[CH2:43][CH3:44])=[O:6])([CH3:3])[CH3:2].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.O.[NH2:60][NH2:61]>CCO>[CH:1]([O:4][C:5]([N:7]1[C:16]2[C:11](=[N:12][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:14][CH:15]=2)[C@H:10]([N:21]([CH2:28][C:29]2[CH:34]=[C:33]([C:35]([F:36])([F:37])[F:38])[CH:32]=[C:31]([C:39]([F:42])([F:41])[F:40])[CH:30]=2)[C:22]2[CH:23]=[C:24]([CH3:25])[NH:61][N:60]=2)[CH2:9][C@@H:8]1[CH2:43][CH3:44])=[O:6])([CH3:2])[CH3:3]
Reactant: NN
Reactant: CC[C@H]1C[C@@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)CC(C)=O)c2nc(C(F)(F)F)ccc2N1C(=O)OC(C)C
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CCO
Solvent: O
Product: CC[C@H]1C[C@@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2cc(C)[nH]n2)c2nc(C(F)(F)F)ccc2N1C(=O)OC(C)C
Temperature: 0 °C
Yield: 37.8 %

Procedure:
Add slowly cold (ice bath) absolute EtOH (1.7 mL) to a cooled 0° C. stirred mixture of (+/−)-cis-4-[(3,5-bis-trifluoromethyl-benzyl)-(3-oxo-butyryl)-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid isopropyl ester (221 mg, 0.34 mmol) and phosphorus pentoxide (880 mg, 6.2 mmol). Add hydrazine hydrate (0.105 mL, 3.4 mmol) while keeping the mixture cooled at 0° C. Seal the tube and heat the reaction mixture at 100° C. overnight. Cool down the mixture and remove the solvents under reduced pressure. Partition the residue between water and dichloromethane. Separate the layers and dry the organic phase, filter, and concentrate in vacuo. Purify the residue by silica gel flash chromatography, eluting with hexanes/ethyl acetate, to afford the title compound (82 mg, 38%). MS (ES+): 638 (M+H).
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH3:11])=[CH:9][C:8](=[O:12])[C:4]([C:5]([OH:7])=[O:6])=[C:3]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[Na+].BrBr.[Br:23]C1C(=O)C(Br)=C(C)N(C)C=1C1C=CC=CC=1>CO>[Br:23][C:9]1[C:8](=[O:12])[C:4]([C:5]([OH:7])=[O:6])=[C:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:2]([CH3:1])[C:10]=1[CH3:11]
Reactant: Cc1cc(=O)c(C(=O)O)c(-c2ccccc2)n1C
Reactant: Cc1c(Br)c(=O)c(Br)c(-c2ccccc2)n1C
Agent: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(Br)c(=O)c(C(=O)O)c(-c2ccccc2)n1C

Procedure:
6.0 g of 1,6-dimethyl-2-phenyl-4-oxonicotinic acid is suspended in 200 ml of methanol. 1.0 g of sodium hydroxide is added. As soon as the acid dissolves a solution of 5.52 g of Br2 in 50 ml of methanol is slowly added with stirring. The pH of the reaction mixture is maintained at 8-9 by the addition of extra sodium hydroxide as required. A precipitate of 3,5-dibromo-1,6-dimethyl-2-phenyl-pyrid-4-one forms. This material is collected by filtration and discarded. Acidification of the clear filtrate yields 3.4 g of 5-bromo-1,6-dimethyl-2-phenyl-4-oxonicotinic acid as a white solid. mp=252°-253° C. (acetonitrile).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH2:3][N:4]=[C:5]([NH2:18])[NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][S:14][CH2:15][CH2:16][NH2:17])[N:8]=1>C(#N)C>[F:20][C:2]([F:1])([F:19])[CH2:3][N:4]=[C:5]([NH2:18])[NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][S:14][CH2:15][CH2:16][NH:17][C:7]([NH:8][CH3:9])=[N:6][C:5]#[N:4])[N:8]=1
Reactant: NCCSCc1cccc(NC(N)=NCC(F)(F)F)n1
Solvent: CC#N
Product: CNC(=NC#N)NCCSCc1cccc(NC(N)=NCC(F)(F)F)n1
Reaction time: 18 h
Yield: 82.6 %

Procedure:
Dimethyl(cyanoimido)dithiocarbonate (0.12 g.) was added to a solution of 2-[2-(2,2,2-trifluoroethyl)guanidino]-6-(2-aminoethylthiomethyl)pyridine (0.23 g.) in acetonitrile (5 ml.) and the solution left at room temperature for 18 hours and then evaporated to dryness. The residue was dissolved in 33% w/v methylamine in ethanol (5 ml.) and the solution left at room temperature for 18 hours and then evaporated to dryness. The residue was purified by preparative thin layer chromatography using ethyl acetate/methanol/ammonia 6:1:0.5 v/v/v as the developing solvent to give 2-[2-(2,2,2-trifluoroethyl)guanidino]-6-[2-(2-cyano-3-methylguanidino)ethylthiomethyl]pyridine (0.12 g.) characterised as the hydrogen maleate, m.p. 137°-140° after recrystallisation from acetone.
Reaction SMILES: C([O:4][C@@H:5]1[CH2:29][CH2:28][C@@:27]2([CH3:30])[C@H:7]([CH2:8][CH2:9][C@@H:10]3[C:26]2=[CH:25][CH2:24][C@@:23]2([CH3:31])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:22])[CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH2:6]1)(=O)C.CC(O)=[O:34]>>[OH:4][C@@H:5]1[CH2:29][CH2:28][C@@:27]2([CH3:30])[C@H:7]([CH2:8][CH2:9][C@@H:10]3[C:26]2=[CH:25][C:24](=[O:34])[C@@:23]2([CH3:31])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:22])[CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH2:6]1
Reactant: CC(=O)O
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](OC(C)=O)CC[C@]4(C)C3=CC[C@]12C
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](O)CC[C@]4(C)C3=CC(=O)[C@]12C
Temperature: 50 °C
Yield: 50 %

Procedure:
CrO3 (17.0 g, 170 mmol) was added to a solution of compound 1.8a (17 g, 39.5 mmol) in AcOH (270 mL). The resulting mixture was heated at 50° C. for 24-36 h. Upon complete disappearance of the starting material by TLC, the solvent was evaporated under vacuum and the crude material was dissolved in ethyl acetate (400 mL) and water (200 mL). The two phases were separated and the organic layer was washed twice with water (2×100 mL) and then once with saturated brine solution (100 mL). The organic phase was dried over anhydrous Na2SO4 (40 g) and filtered. The filtrate was concentrated under vacuum and the resulting solid was purified by column chromatography [49 mm (W)×600 mm (L), 60-120 mesh silica, 120 g], eluting with ethyl acetate/hexane (1:5) [10 mL fractions, 3 mL/min elution, monitored by TLC and detected with UV light (254 nm) lamp]. The product-containing fractions were combined and concentrated under vacuum to afford compound 1.9a (8.8 g, 50% yield) as a white solid.
Reaction SMILES: CCCCCC.C([Li])CCC.Br[C:13]1[CH:18]=[C:17]([CH3:19])[C:16]([CH:20]([S:29][C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)[C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[F:28])=[CH:15][N:14]=1.CN(C)[CH:39]=[O:40]>C1(C)C=CC=CC=1.C(OCC)(=O)C.O>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([S:29][CH:20]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[F:28])[C:16]2[C:17]([CH3:19])=[CH:18][C:13]([CH:39]=[O:40])=[N:14][CH:15]=2)=[CH:31][CH:32]=1
Reactant: Cc1cc(Br)ncc1C(Sc1ccc(Cl)cc1)c1cc(F)ccc1F
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: Cc1cc(C=O)ncc1C(Sc1ccc(Cl)cc1)c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In an argon atmosphere, a hexane solution of n-butyllithium (1.60 M, 2.52 ml, 4.03 mmol) was added to a solution of 2-bromo-5-[[(4-chlorophenyl)thio](2,5-difluorophenyl)methyl]-4-methylpyridine (1.48 g, 3.36 mmol) in toluene (40 ml) at −78° C. The reaction mixture was stirred for 1 hour, and then N,N-dimethylformamide (0.312 ml, 4.03 mmol) was added at the same temperature. After stirring the reaction mixture for 30 minutes, water was added thereto at the same temperature, and the mixture was allowed to warm to room temperature. Ethyl acetate was added to the reaction mixture, and the resulting mixture was washed with saturated aqueous ammonium chloride, and then with saturated brine. The organic layer was dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was subjected to flash silica gel chromatography. The fraction obtained from an elution with hexane:ethyl acetate=10:1 was concentrated under reduced pressure, to obtain the title compound mg, 1.07 mmol, 32%) as a white solid.
Reaction SMILES: [BH4-].[Na+].[C:3]([Si:7]([CH3:21])([CH3:20])[O:8][C@H:9]([C:13]([CH3:19])([CH3:18])[C:14](=[O:17])[CH2:15][CH3:16])[CH2:10][CH:11]=[O:12])([CH3:6])([CH3:5])[CH3:4].N1C=CN=C1.[Si:27](Cl)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28].[Cl-].[NH4+]>C(Cl)Cl.O.C(O)C>[C:3]([Si:7]([CH3:20])([CH3:21])[O:8][C@@H:9]([CH2:10][CH2:11][O:12][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[C:13]([CH3:19])([CH3:18])[C:14](=[O:17])[CH2:15][CH3:16])([CH3:5])([CH3:4])[CH3:6]
Reactant: CCC(=O)C(C)(C)[C@H](CC=O)O[Si](C)(C)C(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCO
Solvent: O
Product: CCC(=O)C(C)(C)[C@H](CCO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.6 %

Procedure:
Sodium borohydride (570 mg, 15.4 mmol, 2 equiv) was dissolved in methylene chloride (175 ml) and dry ethanol (75 ml). The mixture was cooled to −78° C. for 15 min after which a solution of aldehyde 76 (2.2 g, 7.7 mmol, 1 equiv) in methylene chloride (5 ml) was added. After stirring for 1 h water (6 ml) was added and the reaction mixture was allowed to warm to room temperature. Methylene chloride (400 ml) was added and the mixture was washed with saturated aqueous sodium bicarbonate before it was dried over anhydrous sodium sulfate and concentrated in vacuo to give crude alcohol mixture 77 and 78. The crude alcohol mixture was dissolved in methylene chloride (40 ml) and cooled to 0° C. Imidazole (3.14 g, 46.15 mmol, 6 equiv) and tert-butyldimethylsilyl chloride (3.47 g, 23.1 mmol, 3 equiv) were added and the reaction mixture was stirred at room temperature for 16 hr. Saturated aqueous ammonium chloride (30 ml) was added and the layers were separated. The aqueous layer was further extracted with ethyl acetate (3×30) and combined organic extracts were dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash chromatography (1%-5% EtOAc/Hexanes) gave the bis(silylether) 68 (2.5 g, 81% over two steps) as a colorless oil: [α]22D=−7.4 (c=1.8, CHCl3); TLC Rf=0.70 (silica gel, 20% EtOAc/hexanes); 1H NMR (600 MHz, CDCl3) δ 4.058-4.022 (dd, 1H), 3.62-3.54 (m, 2H), 2.57-2.50 (dq, 1H), 2.48-2.40 (dq, 1H), 1.53-1.41 (m, 2H), 1.085 (s, 3H), 1.022 (s, 3H), 0.985-0.96 (t, 3H), 0.86-0.85 (d, 18H), 0.067 (s, 3H), 0.018 (s, 3H), 0.013 (s, 3H), 0.002 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 215.783, 73.613, 60.286, 53.247, 37.458, 31.76, 26.276, 26.116, 22.386, 20.199, 18.533, 18.441, 7.941, −3.805, −3.834, −5.105; HRMS calcd for C21H46O3Si2+Na+ 425.2883; found 425.2885 [M+Na+].
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:9]=3[CH2:8][C:7](=O)[C:6]=2[CH:18]=1.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(=O)(O)[O-].[Na+].O>C1C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:9]=3[CH:8]=[C:7]([N:23]3[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]3)[C:6]=2[CH:18]=1
Reactant: Cc1ccc2c(c1)CC(=O)c1cc(F)ccc1S2
Reactant: CN1CCNCC1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: Cc1ccc2c(c1)C=C(N1CCN(C)CC1)c1cc(F)ccc1S2

Procedure:
18 g of 8-fluoro-2-methyl-dibenzo[b,f]thiepin-10(11H)one in 140 ml of absolute benzene are together with 33.2 ml of N methylpiperazine within 1/2 hour at 20°-25° treated with a solution of 5.8 ml of titanium tetrachloride in 40 ml of absolute benzene. The reaction mixture is subsequently heated for 20 hours under reflux conditions. The reaction mixture is poured, with vigorous stirring, into a mixture of 40 ml of saturated aqueous sodium bicarbonate solution and 120 ml of water, subsequently filtered and extracted with chloroform. The organic phase is dried and evaporated. One obtains 1-(8-fluoro-2-methyl-dibenzo[b,f]thiepin-10-yl)-4-methyl-piperazine, which is converted into the corresponding maleate by treatment with maleic acid. The maleate melts at 244° with decomposition.
Reaction SMILES: C[O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([CH3:23])[N:7]2[CH2:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1.B(Br)(Br)Br.C(Cl)Cl>CCOC(C)=O.CCCCCC>[OH:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([CH3:23])[N:7]2[CH2:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: COc1cccc2c1cc(C)n2Cc1cccc2ccccc12
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1cc2c(O)cccc2n1Cc1cccc2ccccc12
Yield: 71 %

Procedure:
By the method used in Example 1, Part D, 1.17 g (3.9 mmol) of 4-methoxy-2-methyl-1-[(1-naphthalenyl)methyl]-1H-indole was O-demethylated by treating it with 15.6 mL of 1M BBr3 /CH2Cl2 to give a material that was chromatographed on silica gel (eluted with 20% EtOAc/hexane then 50% EtOAc/hexane) to give 796 mg (71% yield) of 4-hydroxy-2-methyl-1-[(1-naphthalenyl)methyl]-1H-indole.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[C@@H:14]3[CH2:15][C@@H:11]([CH:12]=[CH:13]3)[C@@H:10]2[C:16]([NH2:18])=[O:17])[C:5]([C:19]([F:22])([F:21])[F:20])=[CH:4][N:3]=1.[CH3:23][O:24][CH2:25][CH2:26][N:27]1[CH2:33][CH2:32][C:31]2[CH:34]=[C:35]([NH2:38])[CH:36]=[CH:37][C:30]=2[CH2:29][CH2:28]1>>[CH3:23][O:24][CH2:25][CH2:26][N:27]1[CH2:28][CH2:29][C:30]2[CH:37]=[CH:36][C:35]([NH:38][C:2]3[N:7]=[C:6]([NH:8][C@@H:9]4[C@@H:14]5[CH2:15][C@@H:11]([CH:12]=[CH:13]5)[C@@H:10]4[C:16]([NH2:18])=[O:17])[C:5]([C:19]([F:22])([F:21])[F:20])=[CH:4][N:3]=3)=[CH:34][C:31]=2[CH2:32][CH2:33]1
Reactant: NC(=O)[C@@H]1[C@H](Nc2nc(Cl)ncc2C(F)(F)F)[C@H]2C=C[C@@H]1C2
Reactant: COCCN1CCc2ccc(N)cc2CC1
Product: COCCN1CCc2ccc(Nc3ncc(C(F)(F)F)c(N[C@H]4[C@@H](C(N)=O)[C@@H]5C=C[C@H]4C5)n3)cc2CC1

Procedure:
The title compound was prepared from (1S,2S,3R,4R)-3-(2-Chloro-5-trifluoromethylpyrimidin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide and 3-(2-methoxyethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine in an analogous manner to Example 933 to afford a yellow solid (41 mg, 70%). Mp: 125-7° C. LCMS (m/e) 517 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 8.13 (s, 1H), 7.48 (d, J=8 Hz, 1H), 7.37-7.17 (m, 3H), 7.05 (d, J=8 Hz, 1H), 6.32 (m, 2H), 6.85 (br s, 1H), 6.63 (br s, 1H), 4.40 (m, 1H), 3.59 (m, 2H), 3.38 (s, 3H), 3.09 (s, 1H), 2.84 (m, 5H), 3.76 (m, 6H), 2.45 (d, J=8 Hz, 1H), 2.20 (d, J=8 Hz, 1H), 1.62 (d, J=8 Hz, 1H).
Reaction SMILES: CN(C)C=O.Cl.[NH2:7][C:8]1[C:13]([Cl:14])=[CH:12][C:11]([OH:15])=[C:10]([Cl:16])[CH:9]=1.[OH-].[K+].[F:19][C:20]([F:24])=[C:21]([F:23])[F:22]>O>[Cl:14][C:13]1[CH:12]=[C:11]([O:15][C:21]([F:23])([F:22])[CH:20]([F:24])[F:19])[C:10]([Cl:16])=[CH:9][C:8]=1[NH2:7]
Reactant: Nc1cc(Cl)c(O)cc1Cl
Reactant: FC(F)=C(F)F
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cc(Cl)c(OC(F)(F)C(F)F)cc1Cl
Temperature: 85 °C
Reaction time: 1 h

Procedure:
A mixture of 100 ml dimethylformamide (DMF), 75 g (0.035 mole) 4-amino-2,5-dichlorophenol, hydrochloride, and 3.0 g (0.05 mole) KOH (pellets ground to powder) was placed in a 500 ml 3-necked round bottom flask fitted with a mechanical stirrer, thermometer and reflux condenser and was stirred for about 1 hour. It was then heated to 85° C. with stirring and 6.0 g (0.06 mole) of tetrafluoroethylene was bubbled in while heating at 85°-90° C. The addition took about 10 minutes. The reactor and contents were cooled in an ice water bath and 200 ml of water were added. The product was extracted with 200 ml methylene chloride and then again with 100 ml methylene chloride. The extracts were combined and the solvents removed by vacuum distillation. A residue (7 g) remained.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH:10]([CH3:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CI.[CH3:18]C([O-])(C)C.[Na+].CCCCCC.CCOC(C)=O>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[C:10]([CH3:18])([CH3:15])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1CN(Cc2ccccc2)CCC1=O
Reactant: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(C)CN(Cc2ccccc2)CCC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-benzyl-3-methyl-piperidin-4-one (7.0 g, 34 mmol) and MeI (2.4 mL) in THF (100 mL) was added NaOt-Bu (4.2 g, 44 mmol) at 0° C. The reaction was slowly allowed to warm to room temperature and stirred overnight. The aqueous layer was extracted with CH2Cl2. The organic extracts were combined, washed with brine and dried over MgSO4. The solution was filtered and concentrated in vacuo to give the crude product. Flash column chromatography (Hexane/EtOAc, gradient) of the residue gave 1-benzyl-3,3-dimethyl-piperidin-4-one, which was converted into 1-benzyl-3,3-dimethyl-piperidin-4-ylamine (2) using the same procedure as in Scheme 1-1. LC/MS m/z: 220 (M+H)+. This material was used without further purification.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[O:11]([CH2:18][C:19](Cl)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])(O)=O.[Na+]>CCOCC.O>[O:20]=[C:19]([NH:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:18][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)CCCN
Reactant: O=C(Cl)COc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)CCCNC(=O)COc1ccccc1
Yield: 53 %

Procedure:
To a stirred mixture of ethyl 4-aminobutanoate hydrochloride (3.4 g) and phenoxyacetyl chloride (2.76 ml) in 50 ml of Et2O and 50 ml of water was added one portion of NaHCO3 (4 2 g). After 2 hr the layers were separated and the organic phase was washed (1N HCl, brine), dried (MgSO4), and filtered. Evaporation of the solvent under vacuum gave 3.1 g (53%) of the title compound as an oil.
Reaction SMILES: [C:1]([C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][C:11]([OH:13])=O)=[CH:7][C:6]=1[F:16])([CH3:4])([CH3:3])[CH3:2].Cl.C(N=C=NCCCN(C)C)C.Cl.[NH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([NH:38][S:39]([CH3:42])(=[O:41])=[O:40])=[C:34]([CH3:43])[CH:33]=1>CN(C)C1C=CN=CC=1.C(N(CC)CC)C>[C:1]([C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][C:11]([NH:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([NH:38][S:39]([CH3:42])(=[O:41])=[O:40])=[C:34]([CH3:43])[CH:33]=2)=[O:13])=[CH:7][C:6]=1[F:16])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cc(CN)ccc1NS(C)(=O)=O
Reactant: CC(C)(C)c1ccc(OCC(=O)O)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Product: Cc1cc(CNC(=O)COc2ccc(C(C)(C)C)c(F)c2)ccc1NS(C)(=O)=O
Yield: 16.6 %

Procedure:
(4-tert-Butyl-3-fluorophenoxy) acetic acid (339 mg, 1.5 mmol), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (EDC) (518 mg, 2.7 mmol), 4-(dimethylamino)pyridine (DMAP) (55 mg, 0.45 mmol), triethylamine (0.836 ml) and N-[4-(aminomethyl)-2-methylphenyl]methanesulfonamide hydrochloride (451 mg, 1.8 mmol) were mixed in the same procedure described in Example 2(b) to give 105 mg (17% yield) of the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([OH:10])=O)[N:5]([CH3:7])[CH:6]=1.C(Cl)(=O)C(Cl)=O.[NH3:17]>C(Cl)Cl.CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH2:17])=[O:10])[N:5]([CH3:7])[CH:6]=1
Reactant: Cn1cc(Br)cc1C(=O)O
Reactant: N
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cn1cc(Br)cc1C(N)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.8 %

Procedure:
To a suspension of 4-bromo-1-methyl-1H-pyrrole-2-carboxylic acid (Matrix Scientific, Columbia, S.C.; 390 mg, 1.91 mmol) in 5 mL of DCM at RT was added oxalyl chloride (2.0 M solution in DCM, 1.912 mL, 3.82 mmol) followed by 3 drops of DMF. After stirring at RT for 30 min, the mixture was concentrated under reduced pressure. The remaining off white solid was cooled with an ice bath, NH3 (0.5 M solution in 1,4-dioxane, 15.3 mL, 7.65 mmol) was added. After stirring at RT for 30 min, the mixture was diluted with 50 mL of EtOAc and washed with 2×15 mL of water. The organic layer was dried over Na2SO4 and concentrated to give 4-bromo-1-methyl-1H-pyrrole-2-carboxamide (329 mg, 85% yield) as a brown crystalline solid that was used without further purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.51 (1H, br.), 7.08 (1H, d, J=1.8 Hz), 7.01 (1H, br.), 6.86 (1H, d, J=1.8 Hz), 3.80 (3H, s). m/z (ESI, +ve) 202.9/204.9 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]2[S:7][CH:8]=[C:9]([C:11]3[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][N:12]=3)[N:10]=2)[CH2:3][CH2:2]1.N.[H][H]>[Ni].CO>[NH2:16][CH2:15][C:14]1[CH:13]=[N:12][C:11]([C:9]2[N:10]=[C:6]([NH:5][CH2:4][CH:1]3[CH2:3][CH2:2]3)[S:7][CH:8]=2)=[CH:18][CH:17]=1
Reactant: [H][H]
Reactant: N#Cc1ccc(-c2csc(NCC3CC3)n2)nc1
Agent: [Ni]
Agent: N
Solvent: CO
Product: NCc1ccc(-c2csc(NCC3CC3)n2)nc1
Temperature: 40 °C
Reaction time: 6 h
Yield: 51.7 %

Procedure:
Add 6-[2-(cyclopropylmethylamino)-thiazol-4-yl]-nicotinonitrile (2.0 g, 7.8 mmol), Raney Nickel (2.0 mL), and 2M ammonia in methanol (200 mL) to a pressure vessel under a nitrogen atmosphere. Pressurize the vessel to 60 psi with hydrogen, and stir the mixture for 6 h at 40° C. Filter the mixture through Celite® and concentrate in vacuo to an oil. Dissolve the oil in EtOAc (300 mL) and saturated ammonium hydroxide (50 mL). Stir the solution for 20 h in a sealed flask at room temperature. Collect the organic layer and concentrate in vacuo. Purify the crude mixture by SCX chromatography followed by chromatography on silica gel (150 g) eluting with DCM/2M ammonia in methanol (99:1 to 85:15 gradient) to obtain the title compound (1.05 g, 51%). MS (ES+) m/z: 261 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[CH2:19][CH2:18][C:5]2([CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3]1.[BH4-].[Na+].C(O)(=O)C>C1COCC1>[OH:1][CH:2]1[CH2:3][CH2:4][C:5]2([CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[CH2:7][CH2:6]2)[CH2:18][CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(=O)CC2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC2(CCC(O)CC2)CC1
Temperature: -5 °C
Reaction time: 1 h

Procedure:
tert-Butyl 9-oxo-3-azaspiro[5.5]undecane-3-carboxylate (1.5 g) was dissolved in THF (7.5 ml) and cooled to −5° C. NaBH4 (0.212 g) was then added and the mixture was stirred for 1 h at room temperature (TLC monitoring). When the reaction was complete, acetic acid was added to the mixture, and the methanol was then distilled off. The residue was taken up in water (50 ml) and extracted with ethyl acetate (2×50 ml). The combined organic phases were dried (Na2SO4) and concentrated under vacuum. The crude product so obtained was purified by column chromatography (silica gel, 30% ethyl acetate/hexane). Yield: 1.2 g (80%)