Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]12([CH2:11][NH:12][C:13]([C:15]3[C:20]([Cl:21])=[CH:19][N:18]=[C:17]([CH2:22][CH2:23][CH2:24][N:25]([CH2:33][CH2:34][CH2:35][O:36]C4CCCCO4)C(=O)OC(C)(C)C)[CH:16]=3)=[O:14])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2>CO.Cl>[ClH:21].[ClH:21].[C:1]12([CH2:11][NH:12][C:13](=[O:14])[C:15]3[C:20]([Cl:21])=[CH:19][N:18]=[C:17]([CH2:22][CH2:23][CH2:24][NH:25][CH2:33][CH2:34][CH2:35][OH:36])[CH:16]=3)[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: CC(C)(C)OC(=O)N(CCCOC1CCCCO1)CCCc1cc(C(=O)NCC23CC4CC(CC(C4)C2)C3)c(Cl)cn1
Agent: Cl
Solvent: CO
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(CCCNCCCO)ncc1Cl
Reaction time: 0.5 h
Yield: 176.2 %

Procedure:
tert-Butyl 3-(4-{[(1-adamantylmethyl)amino]carbonyl}-5-chloropyridin-2-yl)propyl[3-(tetrahydro-2H-pyran-2-yloxy)propyl]carbamate (Example 2(iv)) (0.24 g) was dissolved in a mixture of methanol (10 ml) and 2M aqueous hydrochloric acid solution (10 ml); the solution was left to stand for 0.5 hours. The mixture was concentrated and the residue diluted with 2M aqueous sodium hydroxide solution (25 ml). The mixture was extracted into dichloromethane (3×25 ml) and the combined extracts were concentrated. The residue was dissolved in a solution of hydrogen chloride in 1,4-dioxane (10 ml of a 4M solution) and left to stand for 0.5 hours. The solution was concentrated and the residue suspended in 2M aqueous sodium hydroxide solution (25 ml), extracted into dichloromethane (3×25 ml) and the combined extracts were concentrated. The residue was purified by chromatography on silica gel eluting with dichloromethane:methanol:0.88 aqueous ammonia (89:10:1). The isolated material was dissolved in a solution of hydrogen chloride in 1,4-dioxane (10 ml of a 4M solution) and concentrated; the resultant solid was recrystallised from ethyl acetate/methanol to afford the titled compound (0.115 g) as a colourless solid.
Reaction SMILES: [P:1]([NH2:17])(=[O:16])([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:18]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]([CH3:29])[CH3:28])[C:22]=1[N:30]=[C:31]=[O:32])([CH3:20])[CH3:19].[H-].[Na+]>O1CCCC1>[CH3:20][CH:18]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]([CH3:28])[CH3:29])[C:22]=1[NH:30][C:31]([NH:17][P:1](=[O:16])([O:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[O:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)=[O:32])[CH3:19]
Reactant: NP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)c1cccc(C(C)C)c1NC(=O)NP(=O)(Oc1ccccc1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 66.3 %

Procedure:
To a suspension of diphenyl phosphoramidate (2.0 g, 8.0 mmol) in tetrahydrofuran (20 mL) at 0° C. is added 2,6-diisopropylphenyl isocyanate (1.7 mL, 8.0 mmol). Sodium hydride (0.32 g, 8.0 mmol) is then added portionwise over 15 minutes. The mixture is allowed to warm to room temperature and stirred for 6 hours. The mixture is partitioned between ethyl acetate and water and the aqueous phase is extracted three times with ethyl acetate. The combined organic extracts are washed with brine, dried over magnesium sulfate, and concentrated. Flash chromatography (7:3 hexane/ethyl acetate) affords 2.4 g of a white solid which is recrystallized (ethyl acetate/hexane) to afford 1.6 g of the title compound as a white solid; mp 171°-175° C.
Reaction SMILES: [ClH:1].[F:2][C:3]1([F:16])[CH2:7][CH2:6][C@@H:5]([NH:8]C(=O)OC(C)(C)C)[CH2:4]1>O1CCOCC1>[ClH:1].[F:2][C:3]1([F:16])[CH2:7][CH2:6][C@@H:5]([NH2:8])[CH2:4]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCC(F)(F)C1
Agent: Cl
Solvent: C1COCCO1
Product: N[C@@H]1CCC(F)(F)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
Hydrochloric acid (4M in dioxane, 60 mL) was added to a solution of (R)-tert-butyl 3,3-difluorocyclopentylcarbamate (4.61 g, 20.8 mmol) in dioxane (40 mL) at 0° C. After complete addition, the reaction mixture was allowed to warm to room temperature and stirred for 2 hours. The solvent was removed in vacuo and the residue was triturated with diethylether to afford the title compound as an off-white solid (2.68 g, 82% yield).
Reaction SMILES: C(OP([CH2:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[C:13]([CH2:18][CH2:19][CH3:20])=[C:12]([O:21][CH3:22])[CH:11]=1)(=O)OCC)C.[H-].[Na+].[F:25][C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH:28]=O.O>C1COCC1>[CH3:17][O:16][C:14]1[CH:15]=[C:10]([CH:9]=[CH:28][C:27]2[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=2[F:25])[CH:11]=[C:12]([O:21][CH3:22])[C:13]=1[CH2:18][CH2:19][CH3:20]
Reactant: O=Cc1ccccc1F
Reactant: CCCc1c(OC)cc(CP(=O)(OCC)OCC)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCc1c(OC)cc(C=Cc2ccccc2F)cc1OC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of diethyl(3,5-dimethoxy-4-1-propylbenzyl)phosphonate (0.50 g, 1.5 mmol) in THF (10 mL) at 0° C. was added NaH (60% in mineral oil) (0.14 g, 3.5 mmol) under N2. After the addition was completed, the suspension was stirred at 0° C. for 1 h and then 2-fluorobenzaldehyde (0.2 mL, 1.9 mmol) in THF (10 mL) was added. The reaction was kept at 0° C. for 1 h and then at 50° C. for 5 h. The reaction was cooled to 0° C. Water (5 mL) was added slowly to quench the reaction followed by addition of 2N HCl (8 mL). The mixture was extracted with ether (3×20 mL). The extract was dried over anhydrous Na2SO4. Evaporation of ether followed by flash chromatography using 5% ethyl acetate in hexane as eluent afforded 2-(3,5-dimethoxy-4-1-propylphenyl)-1-(2-fluorophenyl)ethene (1). (0.31 g, 68%) as a yellow crystal. 1HNMR (CDCl3, ppm): δ 1.34 (d, J=7.1 Hz, 6H), 3.60 (qint. J=7.1 Hz, 1H), 3.89 (s, 6H), 6.74 (s, 2H), 7.0-7.2 (m, 5H), 7.4-7.6 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:12])[CH3:11])[CH:5]=[C:6]([Br:8])[CH:7]=1.Cl[C:14]1[N:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][N:15]=1.CC1C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[Br:8][C:6]1[CH:5]=[C:4]([NH:9][C:10](=[O:12])[CH3:11])[CH:3]=[C:2]([NH:1][C:14]2[N:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][N:15]=2)[CH:7]=1
Reactant: FC(F)(F)c1ccnc(Cl)n1
Reactant: CC(=O)Nc1cc(N)cc(Br)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Product: CC(=O)Nc1cc(Br)cc(Nc2nccc(C(F)(F)F)n2)c1
Temperature: 100 °C
Reaction time: 18 h
Yield: 50.9 %

Procedure:
To a solution of N-(3-amino-5-bromophenyl)acetamide (3.25 g, 14.19 mmol) and 2-chloro-4-(trifluoromethyl)pyrimidine (2.054 mL, 17.03 mmol) in dioxane (8.5 mL) under nitrogen, was added pTsOH (2.70 g, 14.19 mmol). The reaction was stirred at 100° C. for 18 h, cooled to at room temperature. Solvent was removed under reduced pressure and the resultant residue was diluted with sat. NaH-CO3 (aq) and DCM. The organic was dried over sodium sulfate and was concentrated to dryness. Purified by flash chromatography (1:1 to 0:100 hexanes:ethyl acetate) to yield N-(3-bromo-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)acetamide (2.71 g, 7.22 mmol, 51%) as a beige powder. MS APCI: [M+H]m/z 377.0.
Reaction SMILES: O[C@H](CCCC1C=CC(OC)=CC=1)C(O)=O.[OH:17][CH:18]([CH2:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20]>>[OH:17][C@H:18]([CH2:24][CH2:25][CH2:26][C:27]1[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)C(O)CCCc1ccc(OC)cc1
Agent: COc1ccc(CCC[C@@H](O)C(=O)O)cc1
Product: CCOC(=O)[C@H](O)CCCc1ccc(OC)cc1

Procedure:
Using (2R)-2-hydroxy-5-(4-methoxy-phenyl)pentanoic acid (80% e.e.), ethyl 2-hydroxy-5-(4-methoxyphenyl)pentanoate was quantitatively obtained (80% e.e.) by a process similar to the process described in Reference Example 27. The optical purity analysis conditions are as follows: Column: AD-H (Chiralcel, DAICEL Chemical Industries Ltd.)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=1.[CH2:10]([N:14]1[N:18]=[C:17]2[CH:19]=[CH:20][C:21]([CH3:23])=[CH:22][C:16]2=[N:15]1)[CH2:11][C:12]#[CH:13]>>[F:9][CH2:8][C:4]1[N:3]=[C:2]([C:13]#[C:12][CH2:11][CH2:10][N:14]2[N:18]=[C:17]3[CH:19]=[CH:20][C:21]([CH3:23])=[CH:22][C:16]3=[N:15]2)[CH:7]=[CH:6][CH:5]=1
Reactant: FCc1cccc(Br)n1
Reactant: C#CCCn1nc2ccc(C)cc2n1
Product: Cc1ccc2nn(CCC#Cc3cccc(CF)n3)nc2c1
Yield: 40 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-6-(fluoromethyl)-pyridine (73 mg, 0.39 mmol) and 2-but-3-ynyl-5-methyl-2H-benzo[d][1,2,3]triazole (65 mg, 0.35 mmol). Reaction time: 3 hours. The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 40 mg (0.14 mmol, 39%) of 2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-5-methyl-2H-benzo[d][1,2,3]triazole as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15](Br)[CH:16]=2)[N:11]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[C:48]([O:52][CH2:53][CH3:54])(=[O:51])[CH:49]=[CH2:50].Cl>C(N(CCCC)CCCC)CCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH:50]=[CH:49][C:48]([O:52][CH2:53][CH3:54])=[O:51])[CH:16]=2)[N:11]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2)c2ccc(Br)cc21
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCCCN(CCCC)CCCC
Product: CCOC(=O)C=Cc1ccc2c(c1)N(C(=O)OC(C)(C)C)CCN2Cc1ccccc1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
A mixture of 4-benzyl-7-bromo-1,2,3,4-tetrahydro-quinoxaline-1-carboxylic acid tert-butyl ester (2.4 g, Reference Example 5), tri-o-tolylphosphine (96 mg), palladium(II) acetate (24 mg) and ethyl acrylate (1.3 ml) in tributylamine (20 ml) was heated to 110° C. After stirring for 2 hours at 110° C. the mixture was treated with further portions of ethyl acrylate (1.3 ml), tri-o-tolylphosphine (96 mg) and palladium(II) acetate (24 mg) and stirring was continued for a further 16 hours at 110° C. The mixture was then treated with ethyl acrylate (2.6 ml) and stirring was continued for a further 5 hours at 110° C. The reaction mixture was cooled to room temperature then acidified to pH 2 by addition of hydrochloric acid (50 ml, 1N) and then extracted three times with ethyl acetate (50 ml). The combined organic extracts were washed with an aqueous saturated solution of sodium hydrogen carbonate (20 ml), then three times with water (20 ml), then dried over magnesium sulphate and then evaporated under reduced pressure (2.7 kPa) at 40° C. The resulting brown oil (5 g) was subjected to flash chromatography on silica (0,040-0,063 mm) eluting with a mixture of cyclohexane and ethyl acetate (9:1, v/v) to give the title compound (1.83 g) as a yellow oil. 1H NMR, 400 MHz, (CD3)2SO: δ1.3 (t, 3H); 1.5 (s, 9H); 3.5 (broad t, 2H); 3.8 (broad t, 2H); 4.15 (q, 2H); 4.65 (s, 2H); 6.25 (d, J=16 Hz, 1H); 6.65 (d, J=8 Hz, 1H); 7.3 (m, 4H); 7.4 (t, 2H); 7.5 (d, J=16 Hz, 1H); 7.7 (broad s, 1H). MS (EI): M+ 422 (50%), 366 (60%), 322 (40%), 277 (20%), 231 (40%), 185 (10%), 157 (15%), 91 (100%), 57 (40%).
Reaction SMILES: Cl.[CH3:2][O:3][CH2:4][CH2:5][CH2:6][C:7]1[N:11]=[C:10]([CH2:12][N:13]2[C:18]3[CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[S:21][C:17]=3[C:16](=[O:28])[N:15]([CH:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[C:14]2=[O:35])[O:9][N:8]=1.[CH2:36]([O:38][C:39]1[C:48]([O:49][CH3:50])=[CH:47][C:46]2[C:45]([C:51]3[CH:59]=[CH:58][C:54]([C:55](O)=[O:56])=[CH:53][CH:52]=3)=[N:44][C@@H:43]3[CH2:60][CH2:61][S:62][CH2:63][C@@H:42]3[C:41]=2[CH:40]=1)[CH3:37].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:36]([O:38][C:39]1[C:48]([O:49][CH3:50])=[CH:47][C:46]2[C:45]([C:51]3[CH:52]=[CH:53][C:54]([C:55]([N:32]4[CH2:31][CH2:30][CH:29]([N:15]5[C:16](=[O:28])[C:17]6[S:21][C:20]([C:22]7[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=7)=[CH:19][C:18]=6[N:13]([CH2:12][C:10]6[O:9][N:8]=[C:7]([CH2:6][CH2:5][CH2:4][O:3][CH3:2])[N:11]=6)[C:14]5=[O:35])[CH2:34][CH2:33]4)=[O:56])=[CH:58][CH:59]=3)=[N:44][C@@H:43]3[CH2:60][CH2:61][S:62][CH2:63][C@@H:42]3[C:41]=2[CH:40]=1)[CH3:37]
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCSC[C@H]21
Reactant: COCCCc1noc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N3CCC(n4c(=O)c5sc(-c6ccccc6)cc5n(Cc5nc(CCCOC)no5)c4=O)CC3)cc1)=N[C@@H]1CCSC[C@H]21

Procedure:
1-{[3-(3-methoxypropyl)-1,2,4-oxadiazol-5-yl]methyl}-6-phenyl-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride (210 mg; compound B90) is reacted with 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (159 mg; compound C10) and HBTU (167 mg) in DCM (3.5 ml) in the presence of DIPEA (207 mg) according to the procedure described in example 2 to afford the title compound after purification by flash column chromatography [amino phase silica gel, eluent: EtOAc] as a solid.
Reaction SMILES: B.N1CCC[C@H]1C(O)=O.Cl.[Cl:11][C:12]1[C:22]2[N:21]([CH3:23])[C:20](=[O:24])[CH:19]3[CH2:25][CH2:26][CH2:27][N:18]3[C:17](=O)[C:16]=2[CH:15]=[C:14]([O:29][CH3:30])[CH:13]=1>O1CCCC1>[Cl:11][C:12]1[C:22]2[N:21]([CH3:23])[C:20](=[O:24])[CH:19]3[CH2:25][CH2:26][CH2:27][N:18]3[CH2:17][C:16]=2[CH:15]=[C:14]([O:29][CH3:30])[CH:13]=1
Reactant: COc1cc(Cl)c2c(c1)C(=O)N1CCCC1C(=O)N2C
Agent: B
Agent: Cl
Agent: O=C(O)[C@@H]1CCCN1
Solvent: C1CCOC1
Product: COc1cc(Cl)c2c(c1)CN1CCCC1C(=O)N2C

Procedure:
This compound is obtained when a mixture of 1M borane in tetrahydrofuran and 9-chloro-1,2,3,11 a-tetrahydro-7-methoxy-10-methyl-5 H-pyrrolo[2,1-c] [1,4] benzodiazepin-5,11 -(10H)-dione (prepared from proline and 3-chloro-5 -methoxy-N-(methylisatoic anhydride as described in Example 1) are allowed to react as described in Example 1.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[S:21][C:20]3[N:22]4[C:13](=[CH:14][N:15]=[C:16]4[CH:17]=[CH:18][CH:19]=3)[CH:12]=2)=[O:10])[CH2:4]1.C(N(CC)CC)C.Br[CH2:31][CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(O)C>[C:34]1([CH2:33][CH2:32][CH2:31][N:3]2[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]3[S:21][C:20]4[N:22]5[C:13](=[CH:14][N:15]=[C:16]5[CH:17]=[CH:18][CH:19]=4)[CH:12]=3)=[O:10])[CH2:4]2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: BrCCCc1ccccc1
Reactant: O=C(NC1CCNC1)C1=Cc2cnc3cccc(n23)S1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(NC1CCN(CCCc2ccccc2)C1)C1=Cc2cnc3cccc(n23)S1

Procedure:
To a solution of 0.50 g (1.39 mM) of N-(3-pyrrolidinyl)-5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride and 1.0 ml (7.17 mM) of triethylamine in ethanol (5 ml) was added 0.25 ml (1.64 mM) of 1-bromo-3-phenylpropane at room temperature, and the mixture was refluxed under nitrogen for 18 hours. To this reaction mixture was further added 0.2 ml (1.32 mM) of 1-bromo-3-phenylpropane, and the mixture was further refluxed for 3 hours. The solvent was then distilled off under reduced pressure and the residue was diluted with water and extracted with chloroform. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over MgSO4, and purified by column chromatography (methanol/ethyl acetate 20-30%) to provide N-[1-(3-phenylpropan-1-yl)pyrrolidin-3-yl]-5-thia-1,8b-diazaacenaphthylene-4-carboxamide.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:8]([OH:10])=O)=[C:5]([CH3:7])[N:6]=1.O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:22][C:23]1[CH:24]=[C:25]([CH:42]=[CH:43][CH:44]=1)[O:26][C:27]1[CH:28]=[CH:29][C:30]2[N:31]([N:33]=[C:34]([NH:36][C:37]([CH:39]3[CH2:41][CH2:40]3)=[O:38])[N:35]=2)[CH:32]=1>CN(C)C=O.CN(C)C(=O)C>[CH:39]1([C:37]([NH:36][C:34]2[N:35]=[C:30]3[CH:29]=[CH:28][C:27]([O:26][C:25]4[CH:24]=[C:23]([NH:22][C:8]([C:4]5[O:3][C:2]([CH3:1])=[N:6][C:5]=5[CH3:7])=[O:10])[CH:44]=[CH:43][CH:42]=4)=[CH:32][N:31]3[N:33]=2)=[O:38])[CH2:40][CH2:41]1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Reactant: Cc1nc(C)c(C(=O)O)o1
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1nc(C)c(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)nn4c3)c2)o1
Yield: 70.8 %

Procedure:
In the same manner as in Example 18-4 and using 2,4-dimethyl-1,3-oxazole-5-carboxylic acid (127 mg, 0.904 mmol), tetrahydrofuran (8 mL), oxalyl chloride (118 μL, 1.36 mmol), N-[6-(3-aminophenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (70.0 mg, 0.226 mmol), N,N-dimethylformamide (1 drop) and N,N-dimethylacetamide (3 mL) as starting materials, the title compound (69.2 mg, 71%) was obtained as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.CO.[CH2:19]1[O:22][C@H:20]1[CH3:21]>>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][N:14]([CH2:19][C@@H:20]([OH:22])[CH3:21])[CH2:13][CH2:12]1
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)c(F)c1
Reactant: C[C@H]1CO1
Solvent: CO
Product: C[C@H](O)CN1CCN(c2ccc([N+](=O)[O-])cc2F)CC1
Reaction time: 19 h
Yield: 92.7 %

Procedure:
1-(2-Fluoro-4-nitro-phenyl)-piperazine (0.500 g, 0.00222 mol) was dissolved in Methanol (11.0 mL, 0.272 mol) and the reaction mixture was placed in a sealed tube. (S)-(−)-Propylene Oxide (0.235 mL, 0.00335 mol) was then added at room temperature and the reaction was stirred for 19 hours. The reaction was concentrated to yield a yellow solid, (S)-1-[4-(2-Fluoro-4-nitro-phenyl)-piperazin-1-yl]-propan-2-ol (583 mg, 93%). LCMS: m/z=284.10 (M+H+); 1H NMR (400 MHz, DMSO-d6) δ 8.00 (d, 2H, J=11.3 Hz), 7.16 (m, 1H), 4.36 (d, 1H, J=4.0 Hz), 3.80 (m, 1H), 3.28 (m, 4H), 2.57 (m, 4H), 2.26 (m, 2H), 1.06 (d, 3H, J=6.2 Hz).
Reaction SMILES: [F:1][C:2]([F:15])([C:11]([F:14])([F:13])[F:12])[CH2:3][CH2:4][S:5]([CH2:8][C:9]#[N:10])(=[O:7])=[O:6].[F:16][C:17]([S:20][CH2:21][CH2:22]OS(C(F)(F)F)(=O)=O)([F:19])[F:18].C([O-])([O-])=O.[K+].[K+]>COCCOC.O>[F:15][C:2]([F:1])([C:11]([F:12])([F:13])[F:14])[CH2:3][CH2:4][S:5]([CH:8]([CH2:22][CH2:21][S:20][C:17]([F:19])([F:18])[F:16])[C:9]#[N:10])(=[O:6])=[O:7]
Reactant: N#CCS(=O)(=O)CCC(F)(F)C(F)(F)F
Reactant: O=S(=O)(OCCSC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: N#CC(CCSC(F)(F)F)S(=O)(=O)CCC(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (3,3,4,4,4-Pentafluoro-butane-1-sulfonyl)-acetonitrile (WO2007/060839) (0.50 g, 1.99 mmol), trifluoro-methanesulfonic acid 2-trifluoromethylsulfanyl-ethyl ester (WO 2007/147888) (0.55 g, 1.99 mmol), and K2CO3 (0.82 g, 5.97 mmol) in 1,2-dimethoxyethane (20 mL) was stirred under nitrogen at room temperature overnight. The reaction mixture was diluted with H2O (50 mL) and extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, hexanes/EtOAc 19:1) to afford compound II-1 (0.28 g, 37%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:11]2[CH:15]=[CH:14][C:13]([CH:16]=[O:17])=[CH:12]2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[BH4-].[Na+]>CCO>[NH2:1][C:2]1[CH:3]=[C:4]([N:11]2[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12]2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: Nc1cc(-n2ccc(C=O)c2)ccc1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Nc1cc(-n2ccc(CO)c2)ccc1[N+](=O)[O-]

Procedure:
The title compound was prepared from 1-(3-amino-4-nitro-phenyl)-1H-pyrrole-3-carbaldehyde (Example F4) by reduction with 2 eq. NaBH4 in EtOH at 23° C. for 30 min. Obtained as a brown solid (20 mg).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([NH:8][C:9](=[O:13])[O:10][CH2:11][CH3:12])[S:6][CH:7]=1.[O:14]1CCOCC1>O>[OH:14][CH2:2][C:3]1[N:4]=[C:5]([NH:8][C:9](=[O:13])[O:10][CH2:11][CH3:12])[S:6][CH:7]=1
Reactant: C1COCCO1
Reactant: CCOC(=O)Nc1nc(CCl)cs1
Solvent: O
Product: CCOC(=O)Nc1nc(CO)cs1
Reaction time: 3.5 h
Yield: 98.2 %

Procedure:
A mixed solution of ethyl 4-(chloromethyl)-1,3-thiazol-2-ylcarbamate (500 mg) in 1,4-dioxane (5 ml) and water (10 ml) was refluxed with stirring for 3.5 hours. After cooling, it was concentrated under reduced pressure. The mixture was partitioned between ethyl acetate and water. The organic phase was separated, washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (10 g) using a mixed solvent of hexane and ethyl acetate (2:1). The fractions containing the objective compound were collected and evaporated under reduced pressure to give colorless syrup (450 mg, 98.2%).
Reaction SMILES: [CH2:1]1[C:6]2([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][CH:3]([O:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[CH:19]=[C:18]([CH2:23][OH:24])[CH:17]=[CH:16]3)[CH2:2]1.C(Cl)Cl.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>>[CH2:5]1[C:6]2([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]2)[CH2:1][CH2:2][CH:3]([O:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[CH:19]=[C:18]([CH:23]=[O:24])[CH:17]=[CH:16]3)[CH2:4]1
Reactant: OCc1ccc2cc(OC3CCC4(CCCCC4)CC3)ccc2c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=Cc1ccc2cc(OC3CCC4(CCCCC4)CC3)ccc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To [6-(Spiro[5.5]undec-3-yloxy)-naphthalen-2-yl]-methanol (150 mg, 0.46 mmol) in methylene chloride (5 mL, 80 mmol) was added Dess-Martin periodinane (0.274 g, 0.647 mmol) and the resulting solution was stirred at room temperature for 1 hour. The crude reaction was then passed through a silica gel plug, the filtrate was removed under vacuum to give 6-(spiro[5.5]undecan-3-yloxy)-2-naphthaldehyde as a colorless solid. (0.150 g, 100%). 1H NMR (400 MHz, CDCl3) δ 10.09 (s, 1H), 8.25 (s, 1H), 7.92-7.89 (m, 2H), 7.78 (d, J=8.7 Hz, 1H), 7.24-7.19 (m, 2H), 4.48 (m, 1H), 1.96-1.29 (m, 18H).
Reaction SMILES: N[C@@H](C)CNC1SC([C:11](OCC)=[O:12])=C(C)N=1.[NH2:17][CH2:18][C@H:19]([NH:21][C:22]1[S:23][C:24]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:25]([CH3:27])[N:26]=1)[CH3:20]>>[CH3:27][C:25]1[N:26]=[C:22]([N:21]2[C@H:19]([CH3:20])[CH2:18][NH:17][C:11]2=[O:12])[S:23][C:24]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29]
Reactant: CCOC(=O)c1sc(NC[C@H](C)N)nc1C
Reactant: CCOC(=O)c1sc(N[C@H](C)CN)nc1C
Product: CCOC(=O)c1sc(N2C(=O)NC[C@H]2C)nc1C

Procedure:
Following the procedure as described in Preparation 4, making variations as required to replace (S)-ethyl 2-(2-aminopropylamino)-4-methylthiazole-5-carboxylate with (R)-ethyl 2-(1-aminopropan-2-ylamino)-4-methylthiazole-5-carboxylate, the title compound was obtained as a colorless solid (86%): MS (ES+) m/z 269.7 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=[O:5].[C:12](Cl)(=O)C(Cl)=O.CO.C(N(CC)CC)C>ClCCl.CN(C)C=O>[CH3:12][O:5][C:4](=[O:6])[C:3]1[C:7]([CH3:11])=[CH:8][CH:9]=[CH:10][C:2]=1[Cl:1]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1cccc(Cl)c1C(=O)O
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1c(C)cccc1Cl

Procedure:
A solution of 2-chloro-6-methyl-benzoic acid (1.70 g, 10 mmol)) in dichloromethane (10 mL) was treated with oxalyl chloride (6 mL, 12 mmol) and dimethylformamide (several drops) followed by treatment with methanol (10 mL) and triethylamine (2.78 mL, 20 mmol). Workup afforded 2-chloro-6-methyl-benzoic acid methyl ester. The material was used without further purification.