Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][NH:7][S:8]([CH3:11])(=[O:10])=[O:9])=[C:4]([F:14])[CH:3]=1.[C:15]1([O:21][C:22](Cl)=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.N1C=CC=CC=1>O1CCCC1.C(#N)C.C(OCC)(=O)C>[F:14][C:4]1[CH:3]=[C:2]([NH:1][C:22](=[O:23])[O:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=[CH:12][C:5]=1[CH2:6][NH:7][S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: CS(=O)(=O)NCc1ccc(N)cc1F
Reactant: O=C(Cl)Oc1ccccc1
Solvent: C1CCOC1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CS(=O)(=O)NCc1ccc(NC(=O)Oc2ccccc2)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.8 %

Procedure:
To a stirred solution of N-(4-amino-2-fluorobenzyl)methanesulfonamide (190 mg, 0.871 mmol) in tetrahydrofuran and acetonitrile as co-solvent were added phenylchloroformate (0.115 ml, 0.914 mmol) and pyridine (0.084 ml, 1.045 mmol). The reaction mixture was stirred for 1 h at room temperature. The mixture dissolved in ethyl acetate and washed with water and brine. The organic layer was dried over magnesium sulfate and filtered. The filtrate was removed in vacuo. The crude was purified by column chromatography. Phenyl 3-fluoro-4-(methylsulfonamidomethyl)phenylcarbamate (250 mg) was obtained as 85% yield.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)C(=O)C(F)(F)F)[CH2:11][CH2:10][N:9]1[CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH:14][CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[CH2:11][CH2:10][N:9]1[CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN(CCc2ccccc2)[C@H](Cc2ccccc2)C1)C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Product: c1ccc(CCN2CC[C@H](NCc3ccnc4ccccc34)C[C@H]2Cc2ccccc2)cc1

Procedure:
215 mg (0.494 mmol) of (2R*,4S*)-2-benzyl-1-(2-phenylethyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine are reacted with 77 mg (1.97 mmol) of sodium borohydride in analogy to Example 2. The title compound ##STR37## is obtained as oil. TLC: methylene chloride/methanol/conc. ammonia (700:50:1) Rf =0.34, FD-MS: M+ =435.
Reaction SMILES: [C:1]([CH2:3]P(=O)(OCC)OCC)#[N:2].C(=O)([O-])[O-].[K+].[K+].[CH2:18]([N:25]1[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1>[CH2:18]([N:25]1[CH2:30][CH2:29][C:28](=[CH:3][C:1]#[N:2])[CH2:27][CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: CCOP(=O)(CC#N)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#CC=C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of diethyl cyanomethylphosphonate (2.06 g, 11.62 mmol) and anhydrous potassium carbonate (1.6 g, 11.62 mmol) in dry THF (10 mL) was stirred at room temperature for 15 min and then refluxed for 20 min. After cooling to room temperature, benzyl-piperidin-4-one (compound of Example 25; 2 g, 10.56 mmol) was added and the mixture was heated at reflux for 16 h (˜70° C.). The reaction mixture was cooled to room temperature, filtered and quenched with ice water (25 mL). The resulting mixture was extracted with ethyl acetate (2×20 mL) and the combined organic layers were washed with water (2×15 mL) followed by brine (20 mL). The organic phase obtained was dried over anhydrous sodium sulphate and concentrated to obtain a crude product, which was purified by crystallisation using 2% ethyl acetate in hexane to afford the title compound.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[O:25]1[C:29]2[CH:30]=[CH:31][C:32]([CH2:34][NH2:35])=[CH:33][C:28]=2[CH2:27][CH2:26]1.C(N(C(C)C)CC)(C)C.[Cl:45][C:46]1[CH:47]=[N:48][CH:49]=[C:50]([Cl:64])[C:51]=1[S:52][C:53]1[S:57][C:56]([C:58](O)=[O:59])=[CH:55][C:54]=1[N+:61]([O-:63])=[O:62]>ClCCl>[Cl:64][C:50]1[CH:49]=[N:48][CH:47]=[C:46]([Cl:45])[C:51]=1[S:52][C:53]1[S:57][C:56]([C:58]([NH:35][CH2:34][C:32]2[CH:31]=[CH:30][C:29]3[O:25][CH2:26][CH2:27][C:28]=3[CH:33]=2)=[O:59])=[CH:55][C:54]=1[N+:61]([O-:63])=[O:62]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: NCc1ccc2c(c1)CCO2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1ccc2c(c1)CCO2)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Temperature: 25 °C
Reaction time: 6 h
Yield: 5.3 %

Procedure:
2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (76.4 mg, 0.51 mmol), 2,3-dihydrobenzofuran-5-ylmethanamine (165.5 mg, 1.28 mmol) and diisopropylethylamine (12 mg, 0.12 mmol) was added to a suspension of 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (150 mg, 0.43 mmol) in dichloromethane (3 mL) and the resulting mixture was stirred at ambient temperature for 6 hours. TLC analysis showed no acid remaining so the mixture was diluted with dichloromethane and washed with water and brine. The organic layer was dried (Na2SO4), filtered and the solvent was removed to afford a solid. The crude material was purified by silica gel chromatography using a 70:30 mixture of hexane and ethyl acetate as eluent to afford the title product as a brown solid (11 mg, 5% yield). 1H NMR (400 MHz, d6-DMSO) δ: 9.28 (1H, m), 8.99 (2H, m), 8.46 (1H, s), 7.14 (1H, m), 7.00 (1H, m), 6.69 (1H, m), 4.48 (2H, m), 4.30 (2H, m), 3.15 (2H, m). MS m/z: 480.11, 482.11 [M+H]+.
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[S:10][C:11]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:12]=3[CH:13]=2)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:24])=O.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[Cl:24][CH:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:9]1[S:10][C:11]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:12]=2[CH:13]=1
Reactant: OC(c1cc2cc(C(F)(F)F)ccc2s1)C1CCCCC1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: FC(F)(F)c1ccc2sc(C(Cl)C3CCCCC3)cc2c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
To a solution of cyclohexyl[5-(trifluoromethyl)-1-benzothiophen-2-yl]methanol (860 mg) synthesized above in toluene (20 mL) was added thionyl chloride (239 μL), and the mixture was stirred at 100° C. for 1 hr. The reaction mixture was poured into ice-cooled saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give the title object compound (806 mg, 89%) as a pale-brown oil
Reaction SMILES: [F:1][C:2]([S:5][S:6][C:7]([F:10])([F:9])[F:8])([F:4])[F:3].S(=O)(=O)(O)O.[Cl:16]Cl>>[F:1][C:2]([F:4])([F:3])[S:5][Cl:16].[F:1][C:2]([S:5][S:6][C:7]([F:10])([F:9])[F:8])([F:4])[F:3]
Reactant: ClCl
Agent: FC(F)(F)SSC(F)(F)F
Agent: O=S(=O)(O)O
Product: FC(F)(F)SCl
Temperature: 40 °C
Reaction time: 12 h

Procedure:
4,040 g of bis-(trifluoromethyl) -disulfane and 2,000 g of 96% strength sulfuric acid were initially placed in a 10 l Hasteloy autoclave and were charged at 18° C. with a pressure of 5 bar of nitrogen. 1,000 ml of liquid chlorine were pumped into this solution at 40° C. in the course of 2 hours. The reaction mixture was stirred for a further 12 hours at 40° C. and under a pressure of 14 to 16 bar, and it was then purified by distillation. 4,250 g of trifluoromethanesulfenyl chloride having a boiling point of 0° C. at normal pressure and 350 g of unreacted bis-(trifluoromethyl) -disulfane were obtained.
Reaction SMILES: B(Br)(Br)Br.ClCCl.[CH:8]1([CH2:11][N:12]([CH2:34][CH:35]2[CH2:37][CH2:36]2)[C:13]2[C:14]([S:32][CH3:33])=[N:15][N:16]3[C:21]([C:22]4[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[CH:24][C:23]=4[O:30]C)=[CH:20][CH:19]=[CH:18][C:17]=23)[CH2:10][CH2:9]1.C(OCC)(=O)C>ClCCl>[CH:8]1([CH2:11][N:12]([CH2:34][CH:35]2[CH2:37][CH2:36]2)[C:13]2[C:14]([S:32][CH3:33])=[N:15][N:16]3[C:21]([C:22]4[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[CH:24][C:23]=4[OH:30])=[CH:20][CH:19]=[CH:18][C:17]=23)[CH2:9][CH2:10]1
Reactant: COc1cc(C)cc(C)c1-c1cccc2c(N(CC3CC3)CC3CC3)c(SC)nn12
Agent: BrB(Br)Br
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CSc1nn2c(-c3c(C)cc(C)cc3O)cccc2c1N(CC1CC1)CC1CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 50.2 %

Procedure:
A 1 M boron tribromide/dichloromethane solution (0.42 mL) was added to a solution of N,N-dicyclopropylmethyl-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amine (35 mg) in dichloromethane (10 mL) at room temperature under a nitrogen atmosphere, and the mixture was stirred for 10 minutes. The reaction mixture was added to ice water, extraction was performed with ethyl acetate, and the organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and the title compound (17 mg) was obtained from the n-hexane:ethyl acetate (6:1) fraction as white crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:19][OH:20])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1.Cl[C:22]1[CH:23]=[C:24]2[N:31]([CH3:32])[C:30]([CH3:34])([CH3:33])[CH2:29][N:25]2[C:26](=[O:28])[N:27]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([C:15]([F:16])([F:17])[F:18])[CH:14]=1)[CH2:19][O:20][C:22]1[CH:23]=[C:24]2[N:31]([CH3:32])[C:30]([CH3:34])([CH3:33])[CH2:29][N:25]2[C:26](=[O:28])[N:27]=1
Reactant: OCc1ccc(Oc2cncc(C(F)(F)F)c2)c(F)c1
Reactant: CN1c2cc(Cl)nc(=O)n2CC1(C)C
Product: CN1c2cc(OCc3ccc(Oc4cncc(C(F)(F)F)c4)c(F)c3)nc(=O)n2CC1(C)C

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from (3-fluoro-4-((5-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)methanol and 7-chloro-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][C:6]1=[O:10].C(=O)([O-])[O-].[Cs+].[Cs+].[OH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1/[CH:24]=[CH:25]/[CH:26]([CH2:39][CH2:40][C:41]1[CH:46]=[CH:45][C:44]([C:47]([O:49][CH3:50])=[O:48])=[CH:43][CH:42]=1)[CH2:27][CH2:28][C:29]1[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=1>CN(C=O)C>[CH3:50][O:49][C:47]([C:44]1[CH:43]=[CH:42][C:41]([CH2:40][CH2:39][CH:26](/[CH:25]=[CH:24]/[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[O:17][CH2:2][CH2:3][CH2:4][N:5]2[CH2:9][CH2:8][CH2:7][C:6]2=[O:10])[CH2:27][CH2:28][C:29]2[CH:30]=[CH:31][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:37][CH:38]=2)=[CH:46][CH:45]=1)=[O:48]
Reactant: COC(=O)c1ccc(CCC(/C=C/c2ccccc2O)CCc2ccc(C(=O)OC)cc2)cc1
Reactant: O=C1CCCN1CCCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CCC(/C=C/c2ccccc2OCCCN2CCCC2=O)CCc2ccc(C(=O)OC)cc2)cc1
Temperature: 60 °C
Reaction time: 12 h

Procedure:
119 mg (0.74 mmol) of 1-(3-chloropropyl)pyrrolidin-2-one [CAS Reg. No. 91152-30-6] and 240 mg (0.74 mmol) of anhydrous cesium carbonate are added to a solution of 169 mg (0.37 mmol) of methyl 4-[(4E)-5-(2-hydroxyphenyl)-3-{2-[4-(methoxycarbonyl)phenyl]ethyl}pent-4-en-1-yl]benzoate in 2.5 ml of dry DMF, and the mixture is then stirred at 60° C. for 12 h. The mixture is then filtered, and the filtrate is evaporated to dryness. The residue is purified by preparative HPLC. This gives 169 mg (purity 94%, 0.27 mmol, 74% of theory) of a colorless oil.
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[OH:27][C:28]1([C:31](O)=[O:32])[CH2:30][CH2:29]1>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:31]([C:28]3([OH:27])[CH2:30][CH2:29]3)=[O:32])[CH2:24][CH2:25]2)=[CH:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Reactant: O=C(O)C1(O)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1)C1(O)CC1

Procedure:
The title compound, white solid (67 mg, 65%), MS (ISP) m/z=411.3 [(M+H)+], mp 200° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and 1-hydroxy-cyclopropanecarboxylic acid.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:40])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([OH:31])[N:28]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:47]([O:49][C:50](=[O:53])[CH2:51]Br)[CH3:48]>CN(C=O)C.O>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:40])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][CH2:51][C:50]([O:49][CH2:47][CH3:48])=[O:53])[N:28]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:21])([CH3:22])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(O)n(-c3cccc(OC)c3)n2)CC1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cc(C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)N2CCN(C(=O)OCC)CC2)nn1-c1cccc(OC)c1
Temperature: 100 °C

Procedure:
To a solution of 100 mg of 4-((S)-4-tert-Butoxycarbonyl-2-{[5-hydroxy-1-(3-methoxy-phenyl)-1H-pyrazole-3-carbonyl]-amino}-butyryl)-piperazine-1-carboxylic acid ethyl ester in 4 ml of DMF, 116 mg of cesium carbonate and 59 mg of Bromo-acetic acid ethyl ester was added and heated to 100° C. for 3 h. Then, the reaction mixture was diluted with water and filtered through a Chem Elut® cartridge by eluting with ethyl acetate. The solvents were removed under reduced pressure. The crude product was used in the subsequent reaction.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>>[CH3:13][C:10]1[O:9][C:8]([C:7]2[C:2]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[N:3][CH:4]=[CH:5][CH:6]=2)=[N:12][N:11]=1
Reactant: C1CNCCN1
Reactant: Cc1nnc(-c2cccnc2Cl)o1
Product: Cc1nnc(-c2cccnc2N2CCNCC2)o1

Procedure:
This intermediate compound was synthesized from 2-chloro-3-(5-methyl-1,3,4-oxadiazol-2-yl)pyridine (prepared according to J. Heterocyclic Chemistry, 17, 425 (1980)) and piperazine using the procedure of Example 6.
Reaction SMILES: C(O[C@H]1C2C(=CC(OCCC)=CC=2)[C@@H](N)C1)C=C.[CH2:19]([O:22][C@H:23]1[C:31]2[C:26](=[CH:27][C:28]([Br:32])=[CH:29][CH:30]=2)[C@@H:25]([NH2:33])[CH2:24]1)[CH:20]=[CH2:21].[O:34]1[CH2:36][C@@H:35]1[C@@H:37]([NH:45][C:46](=[O:52])[O:47][C:48]([CH3:51])([CH3:50])[CH3:49])[CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[CH2:19]([O:22][C@H:23]1[C:31]2[C:26](=[CH:27][C:28]([Br:32])=[CH:29][CH:30]=2)[C@@H:25]([NH:33][CH2:36][C@@H:35]([OH:34])[C@@H:37]([NH:45][C:46](=[O:52])[O:47][C:48]([CH3:50])([CH3:49])[CH3:51])[CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:24]1)[CH:20]=[CH2:21]
Reactant: C=CCO[C@@H]1C[C@H](N)c2cc(Br)ccc21
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H]1CO1
Agent: C=CCO[C@@H]1C[C@H](N)c2cc(OCCC)ccc21
Product: C=CCO[C@@H]1C[C@H](NC[C@@H](O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)c2cc(Br)ccc21
Yield: 82 %

Procedure:
Step BD (1). (1S,3R)-3-(Allyloxy)-6-bromo-2,3-dihydro-1H-inden-1-amine from Step Z(1) was reacted with tert-butyl (S)-1-((S)-oxiran-2-yl)-2-phenylethylcarbamate (Aldrich) according to the procedures described in Step V (1) to afford, after purification, 275 mg (82% yield) of tert-butyl (2S,3R)-4-((1S,3R)-3-(allyloxy)-6-bromo-2,3-dihydro-1H-inden-1-ylamino)-3-hydroxy-1-phenylbutan-2-ylcarbamate. MS (M+H)+ 531.43. 1H NMR (500 MHz, CDCl3) δ ppm 1.36 (s, 9H) 1.82 (ddd, J=12.67, 6.26, 6.10 Hz, 1H) 2.69-2.79 (m, 3H) 2.87 (dd, J=13.89, 8.09 Hz, 1H) 3.03 (dd, J=14.04, 4.58 Hz, 1H) 3.38-3.46 (m, 1H) 3.79 (s, 1H) 4.01-4.05 (m, 2H) 4.06-4.15 (m, 2H) 4.54 (d, J=9.16 Hz, 1H) 4.75 (t, J=6.10 Hz, 1H) 5.19 (dd, J=10.38, 1.53 Hz, 1H) 5.31 (ddd, J=17.24, 3.20, 1.53 Hz, 1H) 5.94 (ddd, J=22.74, 10.53, 5.49 Hz, 1H) 7.18-7.32 (m, 7H) 7.40 (d, J=8.24 Hz, 1H) 7.50 (s, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].C(=O)([O-])[O-].[K+].[K+].[CH2:18]([CH:20]([CH2:23][CH3:24])[CH2:21][NH2:22])[CH3:19]>CN(C)C=O.C1OCCOCCOCCOCCOCCOC1>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:22][CH2:21][CH:20]([CH2:23][CH3:24])[CH2:18][CH3:19])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Cl
Reactant: CCC(CC)CN
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC(CC)CNc1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 62.6 %

Procedure:
50.0 g (0.26 mol) of 2,5-dichloro-1-nitrobenzene, 71.9 g (0.52 mol) of potassium carbonate, 45.6 g (0.455 mol) of 2-ethylbutylamine and 0.5 g of 18-crown-6 in 250 ml of dimethylformamide were heated at 80° C. for 4 h. The mixture was then poured into a large quantity of ice-water, and the precipitate was filtered off with suction, dried and recrystallized from methanol to yield 41.8 g (63%) of the product.
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]([NH:7][CH2:8][CH2:9][O:10][CH3:11])=[O:6].[H-].[Na+].[NH4+].[Cl-]>C1COCC1.[Cl-].[Na+].O>[CH3:11][O:10][CH2:9][CH2:8][N:7]1[CH2:2][CH2:3][NH:4][C:5]1=[O:6]
Reactant: COCCNC(=O)NCCCl
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: COCCN1CCNC1=O
Temperature: 25 °C
Yield: 91.9 %

Procedure:
A −20° C. solution of 1-(2-chloroethyl)-3-(2-methoxyethyl)urea (0.300 g, 1.661 mmol) in THF (8.3 mL), under Ar, was treated with NaH (60% in mineral oil, 0.166 g, 4.15 mmol) allowed to warm to RT and stirred. The mixture was cooled to 0° C., treated slowly with satd. NH4Cl, then brine, warmed to RT and stirred for 20 min. The layers were separated, the aqueous layer extracted with EtOAc (2×) and the combined organics were dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to afford 1-(2-methoxyethyl)imidazolidin-2-one (220 mg, 92%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 6.26 (s, 1 H), 3.39-3.31 (m, 4 H), 3.22 (s, 3 H), 3.20-3.14 (m, 4 H); MS (ESI) m/z: 145.1 (M+H+).
Reaction SMILES: [CH3:1][N:2]([CH3:39])[C:3](=[O:38])[NH:4][C:5]1[CH:6]=[C:7]([C:11]2[N:20]=[C:19]([NH:21][C:22]3[CH:23]=[C:24]4[C:28](=[CH:29][CH:30]=3)[N:27](C(OC(C)(C)C)=O)[N:26]=[CH:25]4)[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=2)[CH:8]=[CH:9][CH:10]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:27]1[C:28]2[C:24](=[CH:23][C:22]([NH:21][C:19]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]=[C:11]([C:7]4[CH:6]=[C:5]([NH:4][C:3](=[O:38])[N:2]([CH3:1])[CH3:39])[CH:10]=[CH:9][CH:8]=4)[N:20]=3)=[CH:30][CH:29]=2)[CH:25]=[N:26]1
Reactant: CN(C)C(=O)Nc1cccc(-c2nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c3ccccc3n2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)C(=O)Nc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1

Procedure:
To tert-butyl 5-(2-(3-(3,3-dimethylureido)phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (50 mg, 0.10 mmol) was added a solution of 1:1 TFA:CH2Cl2 (3 mL) and stirred at RT for 2 h. The reaction mixture was concentrated in vacuo and left under high vacuum for several hours. The crude product was triturated with ethyl ether and the yellow solid was purified by prep HPLC (method 25-50—70 mins) to afford 3-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenyl)-1,1-dimethylurea. (36 mg, 86%)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13](=[O:14])[C:12]([CH3:16])([CH3:15])[CH2:11][O:10]2)=[C:4]([Cl:17])[CH:3]=1.[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[CH:23]=O>C(O)C>[Cl:17][C:4]1[CH2:3][C:2](=[N:1][CH2:23][C:19]2[S:18][CH:22]=[CH:21][CH:20]=2)[CH:7]=[CH:6][C:5]=1[CH2:8][N:9]1[C:13](=[O:14])[C:12]([CH3:15])([CH3:16])[CH2:11][O:10]1
Reactant: O=Cc1cccs1
Reactant: CC1(C)CON(Cc2ccc(N)cc2Cl)C1=O
Solvent: CCO
Product: CC1(C)CON(CC2=C(Cl)CC(=NCc3cccs3)C=C2)C1=O
Yield: 83.2 %

Procedure:
This compound was prepared in a manner analogous to that of Example 5, using 1.28 grams (0.005 mole) of 2-[(4-amino-2-chlorophenyl)methyl]-4,4-dimethyl-3-isoxazolidinone and 0.56 gram (0.005 mole) of thiophene-2-carboxaldehyde in 25 mL of ethanol. The reaction mixture was concentrated under reduced pressure to a residual oil. The oil was dissolved in anhydrous diethyl ether and was dried for two hours with magnesium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to yield 1.46 grams of 2-[[2-chloro-4-[(thien-2-yl)methylimino]phenyl]-methyl]-4,4-dimethyl-3-isoxazolidinone as an oil.
Reaction SMILES: I.CS[C:4](=[N:19][CH3:20])[NH:5][C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[CH2:21]([NH2:25])[CH2:22][CH2:23][CH3:24].[OH-].[K+].O.O.O.C([O-])(=O)C.[Pb+2].C([O-])(=O)C>C(O)C>[CH2:21]([NH:25][C:4]([NH:19][CH3:20])=[N:5][C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)[CH2:22][CH2:23][CH3:24]
Reactant: CCCCN
Reactant: CN=C(Nc1c(C)cccc1N1CCOCC1)SC
Agent: CC(=O)[O-]
Agent: I
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCCCNC(=Nc1c(C)cccc1N1CCOCC1)NC
Reaction time: 1440 h

Procedure:
A mixture of 2-methyl-1-(6-methyl-2-morpholinophenyl)-3-methyl-2-thiopseudourea hydroiodide (17.8 g), n-butylamine (6.4 g) and ethanol (60 ml) was stored at ambient temperature for 60 days. Potassium hydroxide (2.2 g) and then lead acetate trihydrate (7.6 g) were added and the mixture was heated under reflux for 5 hours to yield 1-(n-butyl)-2-(6-methyl-2-morpholinophenyl)-3-methylguanidine which was converted into its monofumarate salt (m.p. 203°-204° C.) which was recrystallised from a 1:2 mixture of methanol and ether.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:39]=[CH:38][C:18]([CH2:19][N:20]2[C@H:24]([C:25]([OH:27])=[O:26])[CH2:23][C:22]3([CH2:32][CH2:31][N:30]([CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:29][CH2:28]3)[CH2:21]2)=[CH:17][CH:16]=1)[CH2:8][C:9]1[NH:10][CH:11]=[CH:12][N:13]=1.O[CH2:41][C:42]([N:44]([CH3:46])[CH3:45])=[O:43].C(N(C(C)C)CC)(C)C.C(=O)([O-])O.[Na+]>CN(C)C=O>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][N:20]2[C@H:24]([C:25]([O:27][CH2:41][C:42]([N:44]([CH3:46])[CH3:45])=[O:43])=[O:26])[CH2:23][C:22]3([CH2:32][CH2:31][N:30]([CH2:33][C:34]([CH3:35])([CH3:36])[CH3:37])[CH2:29][CH2:28]3)[CH2:21]2)=[CH:38][CH:39]=1)[CH2:8][C:9]1[NH:13][CH:12]=[CH:11][N:10]=1
Reactant: CN(C)C(=O)CO
Reactant: CC(C)(C)CN1CCC2(CC1)C[C@@H](C(=O)O)N(Cc1ccc(CN(Cc3ncc[nH]3)Cc3ncc[nH]3)cc1)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)COC(=O)[C@@H]1CC2(CCN(CC(C)(C)C)CC2)CN1Cc1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.3 %

Procedure:
To an N,N-dimethylformamide (1 mL) solution of the compound (80 mg) obtained in Example 32(5), 2-hydroxy-N,N-dimethylacetoamide (CAS Registry Number: 14658-93-6; 77 mg), diisopropylethylamine (39 μL) and N,N,N′,N′-tetramethyl-O-(7-azobenzotriazol-1-yl)uronium hexafluorophosphate (86 mg) were added. The reaction solution was stirred at room temperature for 16 hours. To this solution, an aqueous saturated sodium hydrogen carbonate solution was added, and the solution was extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (CHROMATOREX NH (trade name), manufactured by Fuji Silysia Chemical Ltd.) (ethyl acetate:methanol=1:0→30:1→15:1) to obtain the title compound (68 mg) having the following physical properties.