Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[C:13]([S:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2)([O-:3])=[O:2].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[S:31])=[CH:25][C:24]=1[C:32]([F:35])([F:34])[F:33]>>[N+:1]([C:4]1[C:13]([S:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:30]([NH:29][C:26]3[CH:27]=[CH:28][C:23]([Cl:22])=[C:24]([C:32]([F:35])([F:33])[F:34])[CH:25]=3)=[S:31])=[CH:17][CH:16]=2)=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2)([O-:3])=[O:2]
Reactant: FC(F)(F)c1cc(N=C=S)ccc1Cl
Reactant: Nc1ccc(Sc2ccc3ncccc3c2[N+](=O)[O-])cc1
Product: O=[N+]([O-])c1c(Sc2ccc(NC(=S)Nc3ccc(Cl)c(C(F)(F)F)c3)cc2)ccc2ncccc12

Procedure:
5-nitro-6-(4-aminophenylthio)quinoline 1.7 mmoles, 0.40 g) and 4-chloro-3-trifluoromethylphenylisothiocyanate 1.7 mmoles, 0.47 g) were reacted according to procedure C to yield the title compound, 0.78 g, 86% product. Mass spec (FD) 534. Calculated for C23H14ClF3 N4O2S2 : C, 51.64; H, 2.64, N, 10.47 Found: C, 51.84; H, 2.73; N, 10.43.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19]CC1C=CC=CC=1>C(O)C.[H][H].[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[OH:19]
Reactant: [H][H]
Reactant: COc1ccccc1CCC=Cc1ccccc1OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: COc1ccccc1CCCCc1ccccc1O
Yield: 60 %

Procedure:
Following a procedure similar to that described in the latter part of Preparation 3, the whole of the benzyl 2-[4-(2-methoxyphenyl)-1-butenyl]phenyl ether prepared as described above was dissolved in 50 ml of ethanol and hydrogenated at 50° C. in an atmosphere of hydrogen at atmospheric pressure and in the presence of 100 mg of 5% w/w palladium-on-charcoal for 6 hours. The crude product thus obtained was purified by column chromatography through silica gel, using 10:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 0.44 g (yield 60%) of the title compound as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][CH:11]=O)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:14][O:15][C:16](=[O:19])[CH2:17][NH2:18].C([BH3-])#N.[Na+]>CO>[CH3:14][O:15][C:16](=[O:19])[CH2:17][NH:18][CH2:11][CH2:10][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH3:9]
Reactant: COC(=O)CN
Reactant: CN(CC=O)C(=O)OC(C)(C)C
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COC(=O)CNCCN(C)C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 48.8 %

Procedure:
To a solution of N-t-butoxycarbonylsarcosinal (1.50 g) and glycine methyl ester hydrochloride (1.63 g) in methanol (60 ml) was added a solution of sodium cyanoborohydride (544 mg) in methanol (10 ml) at ambient temperature. The mixture was stirred overnight at the same temperature. After evaporation of the solvent, the residue was dissolved in ethyl acetate (50 ml), and the solution was washed with 1M sodium bicarbonate solution and water successively, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (chloroform as eluent) to give N-[2-(N-t-butoxycarbonyl-N-methylamino)ethyl]glycine methyl ester (1.04 g) as an oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH:9]([CH2:16][C:17]2[CH:25]=[C:24]([CH3:26])[C:23]3[C:19](=[CH:20][N:21]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[N:22]=3)[CH:18]=2)[CH2:10][C:11]([O:13]CC)=[O:12])[CH:4]=1)[CH3:2].[OH-].[Li+]>O1CCCC1>[CH2:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH:9]([CH2:16][C:17]2[CH:25]=[C:24]([CH3:26])[C:23]3[C:19](=[CH:20][N:21]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:32])([CH3:34])[CH3:33])[N:22]=3)[CH:18]=2)[CH2:10][C:11]([OH:13])=[O:12])[CH:4]=1)[CH3:2]
Reactant: CCOC(=O)CC(Cc1cc(C)c2nn(COCC[Si](C)(C)C)cc2c1)c1cc(CC)ccn1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCc1ccnc(C(CC(=O)O)Cc2cc(C)c3nn(COCC[Si](C)(C)C)cc3c2)c1
Temperature: 60 °C

Procedure:
To a flask containing (±)-ethyl 3-(4-ethylpyridin-2-yl)-4-(7-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-5-yl)butanoate (80 mg, 0.166 mmol, 1.0 equiv) in tetrahydrofuran (4 mL) was added lithium hydroxide (2.0 M, 0.34 mL, 4.0 equiv). The suspension was heated at 60° C. under nitrogen overnight. The reaction mixture was concentrated in vacuo. Hydrochloric acid (1 N, 0.6 mL) was added and the solution was extracted with ethyl acetate. The aqueous solution was adjusted to pH 7 with sodium hydroxide (1 N) and re-extracted with ethyl acetate. The combined ethyl acetate layers were washed with brine, dried over sodium sulfate and concentrated in vacuo to give a light yellow oil. MS (ESI) 454 (MH)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11]S)=[CH:2]1.P(Br)(Br)[Br:14].CCOCC>C(Cl)Cl>[Br:14][CH2:11][CH2:10][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1
Reactant: SCCc1c[nH]c2ccccc12
Reactant: BrP(Br)Br
Solvent: ClCCl
Solvent: CCOCC
Product: BrCCc1c[nH]c2ccccc12

Procedure:
The starting materials of formula II in which X1 is mercapto, --S--SO3Na or --S--SO3K, and R2, R3, R4, R5, R6 and R7 are as defined in the first instance are obtained by the following process: The appropriate compound of formula 11 (X1 =OH) described above, is treated with phosphorus tribromide in an inert solvent, for example, ether or methylene chloride to afford the corresponding 3-(2-bromoethyl)-indole derivative. The latter compound is then converted to the desired starting material of formula II (X1 = SH) by a procedure similar to that described by N. N. Suvorov and V. N. Buyanov, Khim.-Farm. Zh., 1, (1967), [Chem. Abstr. 67, 73474a (1967)], for converting 3-(2-bromoethyl)-indole to indole-3-ethanethiol (II; R2, R3,R4, R5 and R6 = H and X1 = SH). Accordingly, the appropriate 3-(2-bromoethyl)-indole derivative is treated with sodium or potassium thiosulfate to afford the corresponding sodium or potassium β-(3-indoly)ethyl thiosulfate derivative, respectively; namely the desired starting materials of formula II (X=--S--SO3Na or --S--SO3K). Treatment of the latter product with strong alkali, for example, sodium or potassium hydroxide, yields the corresponding bis[ω-(3-indolyl)ethyl]-disulfide derivative. Reduction of the latter compound with lithium aluminum hydride gives the desired compounds of formula II (X1 = SH).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1[CH3:12])#[N:2].[S:13]1[C:22]2[CH2:21][CH2:20][CH2:19][CH2:18][NH:17][C:16]=2[CH:15]=[CH:14]1>>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([N:17]2[CH2:18][CH2:19][CH2:20][CH2:21][C:22]3[S:13][CH:14]=[CH:15][C:16]2=3)=[O:9])=[CH:5][C:4]=1[CH3:12])#[N:2]
Reactant: c1cc2c(s1)CCCCN2
Reactant: Cc1cc(C(=O)O)ccc1C#N
Product: Cc1cc(C(=O)N2CCCCc3sccc32)ccc1C#N

Procedure:
The carboxylic acid from Example C (0.50 g, 3.10 mmol) was reacted with 5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepine (0.45 g, 2.95 mmol) according to the procedure in Example 1A. The product was purified by recrystallisation from EtOAc:pet. ether; yield 0.48 g (55%).
Reaction SMILES: C(N1C(C2SC3CCOC4C=C(C5CN([CH2:27][C:28]([NH2:30])=[O:29])C5)C=CC=4C=3N=2)=NC=N1)(C)C.[NH:31]1[CH2:34][CH:33]([C:35]2[CH:36]=[CH:37][C:38]3[O:47][CH2:46][CH2:45][C:44]4[S:43][C:42]([C:48]5[N:49]([CH:53]([CH3:55])[CH3:54])[N:50]=[CH:51][N:52]=5)=[N:41][C:40]=4[C:39]=3[CH:56]=2)[CH2:32]1.BrCC(N)=O>CN(C=O)C>[CH:53]([N:49]1[C:48]([C:42]2[S:43][C:44]3[CH2:45][CH2:46][O:47][C:38]4[CH:37]=[CH:36][C:35]([CH:33]5[CH2:34][N:31]([CH2:27][C:28]([NH2:30])=[O:29])[CH2:32]5)=[CH:56][C:39]=4[C:40]=3[N:41]=2)=[N:52][CH:51]=[N:50]1)([CH3:54])[CH3:55]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(C3CNC3)cc1-2
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(CC(N)=O)C3)ccc1-2
Agent: NC(=O)CBr
Solvent: CN(C)C=O
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(C3CN(CC(N)=O)C3)cc1-2
Yield: 53 %

Procedure:
Following the procedure of 319, 9-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene and bromoacetamide were reacted in DMF to give 371 (111 mg, 53%). LCMS: RT=6.96 min, [M+H]+=425. 1H NMR δ (ppm) (CDCl3): 8.31 (1H, d, J=2.35 Hz), 7.90 (1H, s), 7.17 (1H, dd, J=8.28, 2.36 Hz), 7.03 (1H, d, J=8.26 Hz), 7.01-6.85 (1H, m), 5.91-5.83 (1H, m), 5.41 (1H, s), 4.37 (2H, t, J=5.06 Hz), 3.89 (2H, t, J=7.36 Hz), 3.81-3.73 (1H, m), 3.43-3.34 (4H, m), 3.22 (2H, s), 1.63 (6H, d, J=6.65 Hz)
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH2:9]([O:11][C:12]([C:14]1[N:15]=[C:16]([Br:22])[N:17]([CH:19]([CH3:21])[CH3:20])[CH:18]=1)=[O:13])[CH3:10].[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[CH:26][CH:25]=1.CCOCC.CCCCCC>C1COCC1>[CH2:9]([O:11][C:12]([C:14]1[N:15]=[C:16]([Br:22])[N:17]([CH:19]([CH3:21])[CH3:20])[C:18]=1[CH:28]([C:27]1[CH:30]=[CH:31][C:24]([Cl:23])=[CH:25][CH:26]=1)[OH:29])=[O:13])[CH3:10]
Reactant: CCOC(=O)c1cn(C(C)C)c(Br)n1
Reactant: O=Cc1ccc(Cl)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCCCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(Br)n(C(C)C)c1C(O)c1ccc(Cl)cc1
Temperature: -20 °C
Reaction time: 2 h

Procedure:
LDA (63 mL, 2M solution in THF, 126 mmol) was slowly (over 30 min) added to a solution of 2-bromo-1-isopropyl-1H-imidazole-4-carboxylic acid ethyl ester (intermediate A; 11.0 g, 42.1 mmol) in THF (200 mL) at −78° C. After 2 h at −78° C., a solution of 4-chlorobenzaldehyde (8.9 g, 63.2 mmol) in THF (10 mL) was slowly added and the reaction mixture was allowed to warm to −20° C. over 30 min. The reaction mixture was quenched at −20° C. with 6 ml of acetic acid, concentrated and taken up in EtOAc/water, extracted twice with EtOAc. The combined organic extracts were washed with water and brine, dried (Na2SO4) and concentrated. The crude material was purified by chromatography (hexane/EtOAc, 60:40) to afford an orange foam. This was treated with 100 ml of 10% Et2O/hexane overnight and the resulting solid was filtered and rinsed with hexane to give the title compound as a white solid. ESI-MS: 403.1 [M+H]+ (LC-MS 2); 1H-NMR (DMSO-d6, 400 MHz) δ ppm 0.90 (d, J=7.04 Hz, 3 H) 1.26 (t, J=7.04 Hz, 3 H) 1.45 (d, J=7.04 Hz, 3 H) 4.25 (qd, J=7.04, 3.13 Hz, 2 H) 4.69 (quin, J=7.04 Hz, 1 H) 6.73 (d, J=4.30 Hz, 1 H) 6.83 (d, J=4.30 Hz, 1 H) 7.27 (m, J=8.60 Hz, 2 H) 7.41 (m, J=8.60 Hz, 2 H); Rf=0.15 (hexane/EtOAc, 60:40)
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[N:13]=[C:14]=[O:15])([CH3:3])[CH3:2].[Br:16]Br.S([O-])([O-])(=O)=O.[Na+].[Na+]>[Fe]>[CH:1]([C:4]1[CH:9]=[C:8]([Br:16])[CH:7]=[C:6]([CH:10]([CH3:11])[CH3:12])[C:5]=1[N:13]=[C:14]=[O:15])([CH3:2])[CH3:3]
Reactant: BrBr
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Agent: [Fe]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Product: CC(C)c1cc(Br)cc(C(C)C)c1N=C=O
Temperature: 120 °C

Procedure:
0.5 g of anhydrous iron-III chloride is added to 203 g of 2,6-diisopropyl-phenyl isocyanate and 162 g of bromine are added dropwise at 20° C. The mixture is then slowly warmed to 120° C until the evolution of gas has ceased. 3.0 g of anhydrous sodium sulfate are then added and the mixture is fractionated in vacuo.
Reaction SMILES: C(OC([N:8]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1)[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18]2([CH3:28])[C:27]3[N:26]=[CH:25][CH:24]=[CH:23][C:22]=3[CH2:21][CH2:20][CH2:19]2)=[CH:12][CH:11]=1)=O)(C)(C)C.N1C=CC=CC=1CNCC1C=CC(CN(CC2NC3C=CC=CC=3N=2)C2(C)C3N=CC=CC=3CCC2)=CC=1>>[N:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[CH2:29][NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][NH:17][C:18]2([CH3:28])[C:27]3[N:26]=[CH:25][CH:24]=[CH:23][C:22]=3[CH2:21][CH2:20][CH2:19]2)=[CH:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(CNC2(C)CCCc3cccnc32)cc1)Cc1ccccn1
Agent: CC1(N(Cc2ccc(CNCc3ccccn3)cc2)Cc2nc3ccccc3[nH]2)CCCc2cccnc21
Product: CC1(NCc2ccc(CNCc3ccccn3)cc2)CCCc2cccnc21

Procedure:
the intermediate from above (121 mg, 0.26 mmol) was converted to the hydrobromide salt with simultaneous deprotection of the BOC group to afford 89 mg (79%) of AMD9361 as a white solid. 1H NMR (D2O) □1.84 (s, 3H), 2.02-2.11 (m, 2H), 2.27-2.35 (m, 1H), 2.44-2.53 (m, 1H), 2.93-3.08 (m, 2H), 4.02 (d, 1H, J=12 Hz), 4.30 (d, 1H, J=12 Hz), 4.50 (s, 2H), 4.75 (s, 2H), 7.50-7.60 (m, 5H), 7.93 (dd, 1H, J=8, 1 Hz), 8.05-8.10 (m, 1H), 8.15 (d, 1H, J=8 Hz), 8.57-8.63 (m, 2H), 8.87 (br d, 1H, J=6 Hz); 13C NMR (D2O) □18.5, 25.7, 27.8, 31.2, 46.2, 47.7, 51.7, 62.6, 125.5, 128.1, 128.4, 131.3, 131.6, 133.1, 136.4, 142.2, 144.4, 145.6, 146.4, 147.1, 150.6. ES-MS m/z 373 (M+H). Anal. Calcd. for C24H28N4.4.6HBr.1.8H2O: C, 37.09; H, 4.69; N, 7.21; Br, 47.30. Found: C, 36.99; H, 4.68; N, 6.99; Br, 47.43. AMD9405: Preparation of N-(2-pyridinylmethyl)-N′-(1H-benzimidazol-2-ylmethyl)-N′-(8-methyl-5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine (free base)
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]([CH3:33])=[C:14]([CH2:16][S:17]([CH:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]3)(=[O:19])=[O:18])[N:15]=2)=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+]>C(O)C>[C:29]([O:28][C:26]([N:23]1[CH2:22][CH2:21][CH:20]([S:17]([CH2:16][C:14]2[N:15]=[C:11]([C:8]3[CH:7]=[CH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:10][CH:9]=3)[O:12][C:13]=2[CH3:33])(=[O:18])=[O:19])[CH2:25][CH2:24]1)=[O:27])([CH3:32])([CH3:30])[CH3:31]
Reactant: COC(=O)c1ccc(-c2nc(CS(=O)(=O)C3CCN(C(=O)OC(C)(C)C)CC3)c(C)o2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1oc(-c2ccc(C(=O)O)cc2)nc1CS(=O)(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Yield: 79.8 %

Procedure:
A solution of tert-butyl 4-((2-(4-(methoxycarbonyl)phenyl)-5-methyloxazol-4-yl)methylsulfonyl)piperidine-1-carboxylate (980 mg, 2.05 mmol, 1.00 equiv), sodium hydroxide (120 mg, 3.00 mmol, 1.50 equiv) in ethanol (10 mL) was stirred at 50° C. overnight in a 100-mL round-bottom flask. The reaction mixture was concentrated under vacuum and quenched by the addition of 30 mL of water/ice. The pH value of the solution was adjusted to 3 with the addition of 3M hydrochloric acid. The precipitate was collected by filtration and dried to give 0.76 g (80%) of 4-(4-((1-(tert-butoxycarbonyl)piperidin-4-ylsulfonyl)methyl)-5-methyloxazol-2-yl)benzoic acid as a white solid. LC-MS: (ES, m/z): 409 [M-C4H9+H]+.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][N:19]=2)=[O:17])=[CH:11][CH:10]=1)C1C=CC=CC=1.OC1C=CC(NC([C@@H]2CCCN2)=O)=CC=1>>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][N:19]=2)=[O:17])=[CH:11][CH:10]=1
Reactant: O=C(Nc1ccc(OCc2ccccc2)cc1)c1n[nH]c2ccccc12
Agent: O=C(Nc1ccc(O)cc1)[C@@H]1CCCN1
Product: O=C(Nc1ccc(O)cc1)c1n[nH]c2ccccc12

Procedure:
This compound was prepared from 1H-Indazole-3-carboxylic acid (4-benzyloxy-phenyl)-amide, using the same method used to prepare (S)-pyrrolidine-2-carboxylic acid (4-hydroxy-phenyl)-amide. The product was purified by flash chromatography, on silica gel, eluted with 5 to 10% methanol in DCM, to give the product as an off white solid, 2.6 g (60% for 2 steps). MS m/z 254 (MH+). 1H NMR (DMSO-d6) δ 6.74 (d, 2H), 7.26-7.34 (m, 1H), 7.43-7.51 (m, 1H), 7.67-7.73 (m, 3H), 8.24 (d, 1H), 9.25 (s, 1H), 10.10 (s, 1H) and 13.72 (s, 1H). Anal. calcd for C14H11N3O2: C, 66.40; H, 4.38; N, 16.59. Found: C, 66.15; H, 4.20; N, 16.82.
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:34][C:35]4[CH:44]=[C:43]5[C:38]([CH:39]=[CH:40][CH:41]=[N:42]5)=[C:37]([F:45])[CH:36]=4)=[N:18][CH:19]=[C:20]([C@H:22]([N:24]4[CH2:29][CH2:28][N:27]([S:30]([CH3:33])(=[O:32])=[O:31])[CH2:26][CH2:25]4)[CH3:23])[CH:21]=3)[N:10]=2)=CC=1.FC(F)(F)C(O)=O>>[NH2:8][C:9]1[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]2[C:17]([NH:34][C:35]3[CH:44]=[C:43]4[C:38]([CH:39]=[CH:40][CH:41]=[N:42]4)=[C:37]([F:45])[CH:36]=3)=[N:18][CH:19]=[C:20]([C@H:22]([N:24]3[CH2:25][CH2:26][N:27]([S:30]([CH3:33])(=[O:31])=[O:32])[CH2:28][CH2:29]3)[CH3:23])[CH:21]=2)[N:10]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc([C@@H](C)N4CCN(S(C)(=O)=O)CC4)cnc3Nc3cc(F)c4cccnc4c3)n2)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(N)nc(-c2cc([C@@H](C)N3CCN(S(C)(=O)=O)CC3)cnc2Nc2cc(F)c3cccnc3c2)n1
Temperature: 75 °C
Yield: 58.1 %

Procedure:
A glass microwave reaction vessel was charged with (R)-N-(3-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-5-(1-(4-(methylsulfonyl)piperazin-1-yl)ethyl)pyridin-2-yl)-5-fluoroquinolin-7-amine (82 mg, 0.105 mmol) and trifluoroacetic acid (1 mL, 13.46 mmol, Aldrich). The reaction mixture was stirred and heated in an oil bath at 75° C. for 14 h. The solvent was removed in vacuo. The residue was treated with 10% MeOH/CH2Cl2 (40 mL). The reaction mixture was washed with sat. NaHCO3 (10 mL), saturated NaCl (10 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as a yellow solid. The crude product was purified by silica gel chromatography eluting with 5% MeOH/CH2Cl2 to give (R)-N-(3-(4-amino-6-methyl-1,3,5-triazin-2-yl)-5-(1-(4-(methylsulfonyl)piperazin-1-yl)ethyl)pyridin-2-yl)-5-fluoroquinolin-7-amine (33 mg, 0.061 mmol, 58.2% yield). 1H NMR (300 MHz, CDCl3) δ 1.47 (d, J=6.72 Hz, 3H) 2.52-2.72 (m, 7H) 2.78 (s, 3H) 3.25 (t, J=4.17 Hz, 4H) 3.60 (q, J=6.53 Hz, 1H) 5.49 (s, 2H) 7.12-7.24 (m, 1H) 7.39-7.54 (m, 1H) 7.83 (d, J=8.33 Hz, 1H) 8.48 (d, J=2.19 Hz, 1H) 8.77 (d, J=2.05 Hz, 1H) 8.96 (d, J=2.34 Hz, 1H) 9.25 (d, J=1.90 Hz, 1H) 12.51 (s, 1H). m/z (ESI, +ve ion) 538.1 (M+H)+.
Reaction SMILES: [O:1]([CH2:9][CH:10]([CH3:37])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:23]([S:24]([NH:27][C:28]3[C:33]([O:34][CH3:35])=[N:32][C:31]([CH3:36])=[CH:30][N:29]=3)(=[O:26])=[O:25])=[CH:22][CH:21]=[CH:20][N:19]=2)=[CH:14][CH:13]=1)[Si](C(C)(C)C)(C)C.C(=O)([O-])O.[Na+].[C:43](O)(=[O:45])[CH3:44]>C(OC(=O)C)(=O)C>[C:43]([O:1][CH2:9][CH:10]([CH3:37])[CH2:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[C:23]([S:24]([NH:27][C:28]3[C:33]([O:34][CH3:35])=[N:32][C:31]([CH3:36])=[CH:30][N:29]=3)(=[O:25])=[O:26])=[CH:22][CH:21]=[CH:20][N:19]=2)=[CH:16][CH:17]=1)(=[O:45])[CH3:44]
Reactant: CC(=O)O
Reactant: COc1nc(C)cnc1NS(=O)(=O)c1cccnc1-c1ccc(CC(C)CO[Si](C)(C)C(C)(C)C)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: COc1nc(C)cnc1NS(=O)(=O)c1cccnc1-c1ccc(CC(C)COC(C)=O)cc1
Temperature: 25 °C

Procedure:
2-[4-(3-hydroxy-2-methylpropyl)phenyl]-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide from Example 19 (100 mg) was heated in a mixture of acetic acid (0.5 ml) and acetic anhydride (0.5 ml) to 80° C. for 10 minutes and allowed to cool to ambient temperature. After 6 hours excess saturated aqueous sodium hydrogen carbonate was added cautiously and the product extracted into ethyl acetate (3×20 ml). The combined organic extract was dried (MgSO4) and evaporated. The residue was purified by elution with a gradient of 0-30% ethyl acetate/hexane through a silica gel Mega Bond Elut column (1 g) to give 2-[4-(3-acetoxy-2-methylpropyl)phenyl]-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (70 mg) as a white foam; 1H NMR (CDCl3): 0.98 (d, 3H), 1.58 (s, 3H), 2.11 (s, 3H), 2.1-2.3 (m, 1H), 2.51 (q, 1H), 2.85 (q, 1H), 3.80 (s, 3H), 3.97 (m, 2H), 6.69 (s, 1H), 7.2 (d, 2H), 7.29 (d, 2H), 8.67 (d, 1H), 8.80 (dd, 1H); mass spectrum (+ve ESP): 471.1 (M+H)+.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[NH:9][CH:8]=[C:7]([CH2:10][CH2:11]O)[C:5]=2[CH:6]=1.S(Cl)(C)(=O)=O.[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.[OH-].[Na+]>C(Cl)Cl.O.CCN(CC)CC>[CH3:18][N:19]1[CH2:24][CH2:23][N:22]([CH2:11][CH2:10][C:7]2[C:5]3[C:4](=[CH:3][CH:2]=[CH:1][CH:6]=3)[NH:9][CH:8]=2)[CH2:21][CH2:20]1
Reactant: OCCc1c[nH]c2ccccc12
Reactant: CN1CCNCC1
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CN1CCN(CCc2c[nH]c3ccccc23)CC1
Temperature: 40 °C
Reaction time: 3 h
Yield: 55.7 %

Procedure:
Tryptophol (0.500 g, 3.10 mmol) and Et3N (1 mL) were dissolved in DCM (2 mL) and then mesyl chloride (0.24 mL, 3.102 mmol) was added dropwise at RT. The reaction was stirred for 3 h and then volatiles were removed in vacuo. The crude mesylate was taken up in DCM (3 mL) and to it was added 1-methylpiperazine (1.72 mL, 15.5 mmol) and Et3N (1 mL). The reaction was heated to 40° C. and stirred overnight. After completion, the reaction mixture was poured into cold water, the pH was adjusted to 10 with 1 N NaOH and the organic products were extracted with DCM (3×15 mL). The combined organic extracts were washed with brine (15 mL), dried with Na2SO4, filtered and concentrated in vacuo. Automated column chromatography method 2 was used to isolate the title compound (0.42 g, 56%). 1H NMR (400 MHz, CDCl3): δ 7.54 (d, J=7.8 Hz, 1H), 7.34 (d, J=8.1 Hz, 1H), 7.10 (t, J=7.1 Hz, 1H), 7.03 (t, J=7.3 Hz, 1H), 6.98 (s, 1H), 2.87 (t, J=7.8 Hz, 2H), 2.58 (t, J=5.9 Hz, 2H), 2.38 (br, 8H), 2.17 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 136.7, 127.4, 121.8, 121.0, 118.3, 118.0, 112.4, 111.0, 58.9, 54.1, 52.2, 44.6, 22.2. ESI-HRMS: calc. for C15H21N3: [M+H]+=244.1808 m/z, found: [M+H]+=244.1797 m/z.
Reaction SMILES: [NH2:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:21]12([CH2:31][C:32](Cl)=[O:33])[CH2:30][CH:25]3[CH2:26][CH:27]([CH2:29][CH:23]([CH2:24]3)[CH2:22]1)[CH2:28]2>>[C:21]12([CH2:31][C:32]([NH:1][N:2]3[C:11](=[O:12])[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[N:4]=[C:3]3[CH2:13][O:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[O:33])[CH2:28][CH:27]3[CH2:26][CH:25]([CH2:24][CH:23]([CH2:29]3)[CH2:22]1)[CH2:30]2
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Reactant: Nn1c(COc2ccccc2)nc2ccccc2c1=O
Product: O=C(CC12CC3CC(CC(C3)C1)C2)Nn1c(COc2ccccc2)nc2ccccc2c1=O

Procedure:
3-Amino-2-phenoxymethyl-4(3H)-quinazolinone and 1-adamantaneacetyl chloride were reacted as described in Example 5 to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.50-1.64 (m, 9H), 1.84 (br s, 3H), 2.03-2.15 (m, 2H), 4.96-5.07 (m, 2H), 6.94-7.03 (m, 3H), 7.27-7.34 (m, 2H), 7.59-7.64 (m, 1H), 7.72 (d, J=7.8 Hz, 1H), 7.87-7.92 (m, 1H), 8.18 (dd, J=8.0, 1.2 Hz, 1H), 10.91 (s, 1H) ppm; MS (DCI/NH3) m/z 444 (M+H)+; Elemental Analysis Calculated for C27H29N3O3.H2O: C, 70.26; H, 6.77; N, 9.10. Found: C, 70.17; H, 6.71; N, 9.23.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH:13]([CH3:15])[CH3:14])[CH2:10][CH2:11]O)=O)(C)(C)C.O=S(Cl)Cl.[CH3:20][C:21]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:22]=1[N:30]=[C:31]=[S:32]>>[CH:13]([C@H:9]1[CH2:10][CH2:11][S:32][C:31](=[N:30][C:22]2[CH:23]=[CH:24][C:25]([N+:27]([O-:29])=[O:28])=[CH:26][C:21]=2[CH3:20])[NH:8]1)([CH3:15])[CH3:14]
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Reactant: CC(C)[C@@H](CCO)NC(=O)OC(C)(C)C
Solvent: O=S(Cl)Cl
Product: Cc1cc([N+](=O)[O-])ccc1N=C1N[C@@H](C(C)C)CCS1
Yield: 100 %

Procedure:
(R)-3-(tert-Butoxycarbonylamino)-4-methylpentanol (Method B6a) was reacted with SOCl2 followed by 2-methyl-4-nitrophenyl isothiocyanate in a manner analogous to Method C2a to afford (R)-4-isopropyl-2-(2-methyl-4-nitrophenylimino)-2,3,4,5-tetrahydro-1,3-thiazine (100%).
Reaction SMILES: [C:1]([N:3]=[C:4](OCC)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:12])#[N:2].[C:16]1([C@H:22]([NH2:24])[CH3:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)C>[C:1]([N:3]=[C:4]([NH:24][C@@H:22]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:23])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:12])#[N:2]
Reactant: C[C@@H](N)c1ccccc1
Reactant: CCOC(Cc1ccccc1C)=NC#N
Solvent: CCO
Product: Cc1ccccc1CC(=NC#N)N[C@H](C)c1ccccc1

Procedure:
A solution of Example 26B (142 mg, 0.7 mmol) and (R)-1-phenylethylamine (85 mg, 0.7 mmol) in absolute ethanol (1 mL) was stirred at 60° C. for 6 h. The mixture was concentrated under reduced pressure and purified by preparative HPLC on a Waters Symmetry C8 column (40 mm×100 mm, 7 μm particle size) using a gradient of 10% to 100% acetonitrile in 10 mM of ammonium acetate over 15 min at a flow rate of 70 mL/min to provide the title compound. MS (ESI+) m/z 277 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.46 (d, J=6.78 Hz, 3H) 2.28 (s, 3H) 3.83 (s, 2H) 5.10 (m, 1H) 6.95 (d, J=8.48 Hz, 1H) 7.16 (m, 3H) 7.29 (m, 1H) 7.35 (m, 5H) 9.37 (d, J=7.46 Hz, 1H).