Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[C:10]([N+:17]([O-])=O)=[CH:9][CH:8]=1.[BH4-].[Na+]>CO>[CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:12]=[C:11]([C:13]([F:16])([F:14])[F:15])[C:10]([NH2:17])=[CH:9][CH:8]=1
Reactant: C[C@H]1CCCN1c1ccc([N+](=O)[O-])c(C(F)(F)F)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C[C@H]1CCCN1c1ccc(N)c(C(F)(F)F)n1
Reaction time: 0.08 h
Yield: 97.3 %

Procedure:
To a solution of (S)-6-(2-methylpyrrolidin-1-yl)-3-nitro-2-(trifluoromethyl)pyridine (300 mg, 1.1 mmoL) in 5 mL methanol was added NiCl2.6H2O (772 mg, 3.3 mmoL). After stirring for 5 min, NaBH4 (84 mg, 2.2 mmoL) was added in three portions at 0° C. The reaction mixture was stirred for 5 min and quenched with water (10 mL) and was extracted with EtOAc (15 mL×3). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, concentrated and purified by silica gel chromatography on silica gel to afford (S)-6-(2-methylpyrrolidin-1-yl)-2-(trifluoromethyl)pyridin-3-amine (260 mg, 92.6% yield).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[F:11][C:12]1[CH:13]=[C:14]([S:19]([CH2:22][C:23]2[CH:28]=[C:27]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][C@@H:30]3[CH3:35])[N:26]=[C:25]([C:36]3[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=3)[N:24]=2)(=[O:21])=[O:20])[CH:15]=[C:16]([F:18])[CH:17]=1.C(=O)([O-])O.[Na+]>O1CCOCC1>[F:11][C:12]1[CH:13]=[C:14]([S:19]([CH2:22][C:23]2[CH:28]=[C:27]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][C@@H:30]3[CH3:35])[N:26]=[C:25]([C:36]3[CH:42]=[CH:41][C:39]([NH:40][C:2](=[O:3])[O:4][C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=4)=[CH:38][CH:37]=3)[N:24]=2)(=[O:20])=[O:21])[CH:15]=[C:16]([F:18])[CH:17]=1
Reactant: C[C@H]1COCCN1c1cc(CS(=O)(=O)c2cc(F)cc(F)c2)nc(-c2ccc(N)cc2)n1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: C[C@H]1COCCN1c1cc(CS(=O)(=O)c2cc(F)cc(F)c2)nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Phenyl chloroformate (0.208 mL, 1.66 mmol) was added to 4-[4-[(3,5-difluorophenyl)sulfonylmethyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]aniline (693 mg, 1.50 mmol) and sodium hydrogen carbonate (190 mg, 2.26 mmol) in dioxane (10 mL). The resulting slurry was stirred at RT for 1 hour. The mixture was partitioned between ethyl acetate and water. The organic solution was dried (MgSO4) and concentrated under reduced pressure. The residue was chromatographed on silica, eluting with 25%-80% ethyl acetate in isohexane, to give the desired product as a yellow dry film (827 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4](O)=[O:5].[CH3:12][NH:13][CH:14]=O>O>[Cl:11][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[N:1]=[CH:12][N:13]([CH3:14])[C:4]2=[O:5]
Reactant: Nc1ccc(Cl)cc1C(=O)O
Reactant: CNC=O
Solvent: O
Product: Cn1cnc2ccc(Cl)cc2c1=O
Temperature: 180 °C
Yield: 65 %

Procedure:
2-amino-5-chlorobenzoic acid 27 (12.5 g, 73 mmol) was placed in a 250 mL beaker containing n-methylformamide (125 mL). A condenser was utilized and the reaction was heated overnight at 180° C. The reaction was complete the next morning and allowed to cool to room temperature for 1 hr and then poured into 500 mL of water and extracted three times with 250 mL of ethyl acetate. The organic phase was then washed with an additional 1 liter of water and concentrated under vacuum to yield 6-chloro-3-methylquinazolin-4(3H)-one (9.2 g, 47.3 mmol, 65% yield) 1H NMR (300 MHz, D6 DMSO): δ 8.39 (s, 1H), 8.04 (d, 1H, J=3.6 Hz), 7.82 (dd, 1H, J=2.4 Hz, J=8.7 Hz), 7.67 (1H, d, J=8.7 Hz), 3.49 (s, 3H). 13C NMR (75 MHz, D6 DMSO): δ 160.49, 149.75, 147.65, 135.06, 131.99, 130.26, 125.61, 123.45, 34.53. ESMS: m/z 195.2 [MH]+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[CH:32]1([CH2:38][N:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:29])([F:31])[F:30])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([N:42]4[CH2:43][CH2:44][N:39]([CH2:38][CH:32]5[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]5)[CH2:40][CH2:41]4)=[O:23])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Reactant: C1CCC(CN2CCNCC2)CC1
Product: O=C(c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1)N1CCN(CC2CCCCC2)CC1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 1-(cyclohexylmethyl)piperazine as in General Procedure 10 to give the title compound. LCMS: m/z=611.96 (M+H+); retention time=0.64 minutes.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].[OH-:10].[Na+].O>C(#N)C>[C:5]([NH:6][C:2]([CH3:9])([CH3:1])[C:3]([OH:10])=[O:8])(=[O:7])[NH2:4]
Reactant: CC1(C)NC(=O)NC1=O
Reactant: [OH-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(C)(NC(N)=O)C(=O)O
Reaction time: 3.5 h
Yield: 74.1 %

Procedure:
First, 4.0 g of 5,5-dimethylhydantoin was mixed with 4.0 g of sodium hydroxide and 4.0 g of water, and the mixture was stirred at 85° C. to 90° C. for 3.5 hours. The HPLC analysis (column: COSMOSIL 5C18-ARII (produced by Nacalai Tesque Inc.), mobile phase: acetonitrile/10 mM aqueous potassium dihydrogen phosphate solution=20/80, flow rate: 0.5 ml/min, detection wavelength: 210 nm, column temperature: 40° C.) of the reaction mixture showed the production of 3.38 g (yield 74.1%) of the title compound.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[C:9]1([CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([C@H:23]3[CH2:40][C@@:38]4([CH3:39])[C@@H:34]([CH2:35][CH2:36][C:37]4=[O:41])[C@H:33]4[C:24]3=[C:25]3[C:30]([CH2:31][CH2:32]4)=[CH:29][C:28](=[O:42])[CH2:27][CH2:26]3)=[CH:19][CH:18]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Na+].[Cl-].C1CCCCC1>CN(C)C=O>[Cl:1][C:29]1[C:28](=[O:42])[CH2:27][CH2:26][C:25]2[C:30]=1[CH2:31][CH2:32][C@@H:33]1[C:24]=2[C@@H:23]([C:20]2[CH:19]=[CH:18][C:17]([O:16][CH2:15][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:22][CH:21]=2)[CH2:40][C@@:38]2([CH3:39])[C@H:34]1[CH2:35][CH2:36][C:37]2=[O:41]
Reactant: O=C1CCC(=O)N1Cl
Reactant: C[C@]12C[C@H](c3ccc(OCc4ccccc4)cc3)C3=C4CCC(=O)C=C4CC[C@H]3[C@@H]1CCC2=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCCCC1
Product: C[C@]12C[C@H](c3ccc(OCc4ccccc4)cc3)C3=C4CCC(=O)C(Cl)=C4CC[C@H]3[C@@H]1CCC2=O
Reaction time: 0.17 h

Procedure:
5.295 g of N-chlorosuccinimide is added at 60° C. under an inert atmosphere to a solution of 13.6 g of 11β-[4-(phenylmethoxy)phenyl]-estra-4,9-diene-3,17-dione in 120 ml of dimethylformamide, agitation is carried out for 10 minutes then the reaction medium is poured into a saturated aqueous solution of NaCl, followed by extraction, washing, drying and evaporating under reduced pressure until the crude product is obtained (m=19.128 g). A second trial is carried out, the crude products are collected and purified by chromatography eluting with an ethyl acetate-cyclohexane mixture 30/70. 23.28 g of expected pure product is obtained. (Rf ACOET/cyclohexane 30/70=0.19).
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[C:12]([CH:16]([O:38][SiH:39]([CH3:41])[CH3:40])[C:17]1[C:18]([CH:35]([CH3:37])[CH3:36])=[N:19][C:20]([CH:32]([CH3:34])[CH3:33])=[C:21]([CH2:30][OH:31])[C:22]=1[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)([CH3:15])([CH3:14])[CH3:13]>C(Cl)Cl>[C:12]([CH:16]([O:38][SiH:39]([CH3:40])[CH3:41])[C:17]1[C:22]([C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)=[C:21]([CH:30]=[O:31])[C:20]([CH:32]([CH3:34])[CH3:33])=[N:19][C:18]=1[CH:35]([CH3:37])[CH3:36])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)c1nc(C(C)C)c(C(O[SiH](C)C)C(C)(C)C)c(-c2ccc(F)cc2)c1CO
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)c1nc(C(C)C)c(C(O[SiH](C)C)C(C)(C)C)c(-c2ccc(F)cc2)c1C=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.24 g (12.4 mmol) of neutral alumina and 2.7 g (12.4 mmol) of pyridinium chlorochromate are added to a solution of 2.7 g (6.2 mmol) of the compound from Example 6 in 50 ml of methylene chloride and the mixture is stirred for 1 h at room temperature. It is filtered over kieselguhr and washed with 200 ml of methylene chloride. The methylene chloride phase is concentrated in vacuo and the residue is chromatographed on a column (100 g of silica gel, 70-230 mesh, φ3.5 cm, using ethyl acetate/petroleum ether 1:9).
Reaction SMILES: [CH3:1][CH:2]([CH3:31])[CH2:3][C@H:4]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:19]3[C:14](=[CH:15][N:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[N:12]([CH3:21])[C:11]=2[CH:22]=1.[Br:32]N1C(=O)CCC1=O>C(#N)C.O>[Br:32][C:8]1[C:7]([O:6][CH2:5][C@@H:4]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:3][CH:2]([CH3:31])[CH3:1])=[CH:22][C:11]2[N:12]([CH3:21])[C:13](=[O:20])[C:14]3[C:19]([C:10]=2[CH:9]=1)=[CH:18][CH:17]=[N:16][CH:15]=3
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)C[C@@H](COc1ccc2c3ccncc3c(=O)n(C)c2c1)NC(=O)OC(C)(C)C
Solvent: CC#N
Solvent: O
Product: CC(C)C[C@@H](COc1cc2c(cc1Br)c1ccncc1c(=O)n2C)NC(=O)OC(C)(C)C
Temperature: 85 °C
Yield: 67.7 %

Procedure:
To a solution of (S)-tert-butyl (4-methyl-1-((6-methyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)pentan-2-yl)carbamate (0.100 g, 0.235 mmol) (as prepared in Ex. 2, Part D) in anhydrous acetonitrile (5 mL) was added N-bromosuccinimide (0.042 g, 0.235 mmol) and the mixture was heated at 85° C. for 5 h. The reaction mixture was diluted with water (10 mL), extracted with ethyl acetate (2×20 mL). The combined organic layers were dried over sodium sulfate and evaporated under reduced pressure to afford crude product which was purified by preparative TLC (gradient of ethyl acetate and petroleum ether) to afford (S)-tert-butyl (1-((9-bromo-6-methyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (80 mg, 0.159 mmol, 68% yield) as an off-white solid. LC/MS (ESI) m/e 504.2 [(M+H)+, calcd for C24H31BrN3O4 504.1]; LC/MS retention time (method A): tR=2.23 min.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([O:19][CH3:20])=[CH:8][C:9]([N+:16]([O-])=O)=[C:10]([CH:15]=1)[C:11]([O:13][CH3:14])=[O:12]>CCOC(C)=O.[Pd]>[NH2:16][C:9]1[CH:8]=[C:7]([O:19][CH3:20])[C:6]([O:5][CH2:4][CH2:3][CH2:2][Cl:1])=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1cc(OCCCCl)c(OC)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(OCCCCl)c(OC)cc1N
Yield: 99.5 %

Procedure:
In the manner described in Example 16A Step 3, methyl 5-(3-chloropropoxy)-4-methoxy-2-nitrobenzoate (6.70 g, 22.1 mmol) in EtOAc (100 mL) was reacted with 10% palladium on carbon as described in Example 16A Step 3 to give methyl 2-amino-5-(3-chloropropoxy)-4-methoxybenzoate (6.0 g, 22.0 mmol, 99%). 1H NMR (300 MHz, DMSO-d6) δ 7.18 (s, 1H), 6.49 (br s, 2H), 6.37 (s, 1H), 3.93 (t, 2H), 3.82-3.71 (m, 8H), 2.14-2.06 (m, 2H); LC-MS (ESI) m/z 274 (M+H)+.
Reaction SMILES: [SH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]([NH:12][C:13](=[O:15])[CH3:14])[CH3:11])=[CH:7][C:6]=2[CH:16]=1.BrC1C=CC2OC(C(NC(=O)C)C)=CC=2C=1.[CH2:33]([O:35][C:36]1[CH:43]=[CH:42][C:39]([CH2:40]Cl)=[CH:38][CH:37]=1)[CH3:34].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.[Cl-].[Na+].O>[CH2:33]([O:35][C:36]1[CH:43]=[CH:42][C:39]([CH2:40][S:1][C:2]2[CH:3]=[CH:4][C:5]3[O:9][C:8]([CH:10]([NH:12][C:13](=[O:15])[CH3:14])[CH3:11])=[CH:7][C:6]=3[CH:16]=2)=[CH:38][CH:37]=1)[CH3:34]
Reactant: CCOc1ccc(CCl)cc1
Reactant: CC(=O)NC(C)c1cc2cc(S)ccc2o1
Agent: CC(=O)NC(C)c1cc2cc(Br)ccc2o1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccc(CSc2ccc3oc(C(C)NC(C)=O)cc3c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the obtained mixture (750 mg) of N-[1-(5-sulfanyl-1-benzofuran-2-yl)ethyl]acetamide and N-[1-(5-bromo-1-benzofuran-2-yl)ethyl]acetamide in anhydrous DMF (6.4 mL) were added 4-ethoxybenzyl chloride (1.09 g, 6.38 mmol) and potassium carbonate (880 mg, 0.456 mmol), and the reaction mixture was stirred at room temperature overnight. Saturated brine was added thereto, and the mixture was extracted twice with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1 to 1:4), and the obtained solid was washed with diethyl ether to give N-(1-{5-[(4-ethoxybenzyl)sulfanyl]-1-benzofuran-2-yl}ethyl)acetamide (205 mg, yield from (N-[1-(5-{[tert-butyl(dimethyl)silyl]oxy}-1-benzothiophen-2-yl)ethyl]acetamide 16%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:19][CH2:18][C:15]([C:20]([O:22]N3C4C=CC=CC=4N=N3)=O)([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:43][C:44]12[CH2:51][CH2:50][C:47]([OH:52])([CH2:48][CH2:49]1)[CH2:46][CH2:45]2>>[CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:17][CH2:16][C:15]([C:20]([NH:43][C:44]34[CH2:51][CH2:50][C:47]([OH:52])([CH2:48][CH2:49]3)[CH2:46][CH2:45]4)=[O:22])([CH2:14][CH2:13]1)[CH2:18][CH2:19]2)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC12CCC(O)(CC1)CC2
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CN(C(=O)OCc1ccccc1)C12CCC(C(=O)On3nnc4ccccc43)(CC1)CC2
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CN(C(=O)OCc1ccccc1)C12CCC(C(=O)NC34CCC(O)(CC3)CC4)(CC1)CC2
Yield: 61.7 %

Procedure:
In a similar manner to Example 4, (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(benzotriazol-1-yl)oxycarbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 4-aminobicyclo[2.2.2]octane-1-ol (13.5 mg) were used to obtain (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-[N-(4-hydroxybicyclo[2.2.2]oct-1-yl)amino]carbonylbicyclo[2.2.2)oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (31.2 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[O:5][C:6]1[N:23]=[CH:22][CH:21]=[CH:20][C:7]=1[C:8]([NH:10][CH2:11][CH:12]([OH:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O.O(Cl)Cl>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[O:5][C:6]1[C:7]([C:8]2[O:19][CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:11][N:10]=2)=[CH:20][CH:21]=[CH:22][N:23]=1
Reactant: O=C(NCC(O)c1ccccc1)c1cccnc1Oc1cccc(Cl)c1
Agent: ClOCl
Solvent: Cc1ccccc1
Product: Clc1cccc(Oc2ncccc2C2=NCC(c3ccccc3)O2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.5 %

Procedure:
A solution of 2-(3-Chloro-phenoxy)-N-(2-hydroxy-2-phenyl-ethyl)-nicotinamide (0.320 grams, 0.868 mmole) and phosprorus oxychloride (0.7 ml) in toluene (10 ml) was stirred over night. The mixture was concentrated to dryness and dissolved in methanol (10 ml) and potassium carbonate was added. The mixture was stirred for 2 hours at room temperature and refluxed for 30 minutes. The methanol was evaporated, and the residue taken up in ethyl acetate. It was washed with water and brine, dried over Na2SO4, and concentrated to give a product that was purified by chromatography on silica gel eluting with 1/3 ethyl acetate/hexane to give a pale yellow oil (0.102 g). HRMS 351.0897; 1H NMR (400 MHz, CDCl3) d 4.06 (dd, J=8.1, 15.0 Hz, 1H), 4.56 (dd, J=10.3, 15.0 Hz, 1H), 5.66 (dd, J=8.0, 10.3 Hz, 1H), 7.24 (m, 10H), 8.8.27 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[N:13]([CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])[C:12]3[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:11]=3[S:10]2)=[CH:5][CH:4]=1.[C:28](OC(=O)C)(=[O:30])[CH3:29].[BrH:35]>N1C=CC=CC=1>[BrH:35].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([O:16][C:28](=[O:30])[CH3:29])[C:14](=[O:17])[N:13]([CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])[C:12]3[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:11]=3[S:10]2)=[CH:5][CH:4]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc([C@@H]2Sc3cc(C)ccc3N(CCN(C)C)C(=O)[C@@H]2O)cc1
Agent: Br
Solvent: c1ccncc1
Product: COc1ccc([C@@H]2Sc3cc(C)ccc3N(CCN(C)C)C(=O)[C@@H]2OC(C)=O)cc1
Temperature: 110 °C
Reaction time: 4 h
Yield: 96 %

Procedure:
A mixture of 5.05 g of (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(dimethylamino)ethyl]-8-methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one, 20 ml of acetic anhydride and 0.1 ml of pyridine is stirred at 110° C. for 4 hours. After the reaction is completed, the mixture is evaporated under reduced pressure to remove acetic anhydride, acetic acid and pyridine. Benzene is added to the residue, and the mixture is evaporated under reduced pressure to remove solvent. The residue thus obtained is converted into its hydrobromide and recrystallized from a mixture of ethanol and ether. 6.374 g of (+)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2-(dimethylamino)ethyl]-8-methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrobromide are obtained. Yield: 96%
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([NH:9][C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]=[C:12]([S:20][C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([O:29]C)=[O:28])[CH:22]=4)[N:11]=3)[NH:7][N:8]=2)[CH2:3][CH2:2]1.[Li+].[OH-].Cl>C1COCC1.O>[C:27]([C:23]1[CH:22]=[C:21]([S:20][C:12]2[N:11]=[C:10]([NH:9][C:6]3[NH:7][N:8]=[C:4]([CH:1]4[CH2:2][CH2:3]4)[CH:5]=3)[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH:26]=[CH:25][CH:24]=1)([OH:29])=[O:28]
Reactant: COC(=O)c1cccc(Sc2nc(Nc3cc(C4CC4)n[nH]3)c3ccccc3n2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cccc(Sc2nc(Nc3cc(C4CC4)n[nH]3)c3ccccc3n2)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of (5-cyclopropyl-2H-pyrazol-3-yl)-[2-(3-methoxycarbonylphenylsulfanyl)-quinazolin-4-yl]-amine (110 mg, 0.26 mmol) in a mixture of THF/water (1/1, 10 mL) is treated with 1M LiOH (0.75 mL, 0.75 mmol). The mixture is stirred for 20 hours at room temperature and then neutralized with 1M HCl (0.75 mL, 0.75 mmol). A solid forms and is collected by filtration to afford the desired [2-(3-carboxyphenylsulfanyl)-quinazolin-4-yl]-(5-cyclopropyl-2H-pyrazol-3-yl)-amine.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH:5]([CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[C:6]([NH:8][NH:9]C(OC(C)(C)C)=O)=[O:7]>Cl.O1CCOCC1>[ClH:1].[Cl:1][CH2:2][CH2:3][CH2:4][CH:5]([CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[C:6]([NH:8][NH2:9])=[O:7]
Reactant: CC(C)(C)OC(=O)NNC(=O)C(CCCCl)C1CCCCC1
Agent: Cl
Solvent: C1COCCO1
Product: NNC(=O)C(CCCCl)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 229.7 %

Procedure:
tert-Butyl N′-(5-chloro-2-cyclohexyl-pentanoyl)-hydrazinecarboxylate (155 mg) was dissolved in a solution of 4 N hydrogen chloride in dioxane (2 ml), and the reaction solution was stirred at room temperature for one hour. The reaction solution was concentrated under reduced pressure to obtain 144 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: [CH:1]([NH:4][S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15])(=[O:7])=[O:6])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:20][CH2:21][CH2:22][N:23]1[C:27](=[O:28])[C:26]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:25]2[C:24]1=[O:33]>CN1CCCC1=O.C(OCC)(=O)C>[O:33]=[C:24]1[C:25]2[C:26](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27](=[O:28])[N:23]1[CH2:22][CH2:21][CH2:20][N:4]([CH:1]([CH3:3])[CH3:2])[S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15])(=[O:7])=[O:6]
Reactant: CC(C)NS(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CC(C)N(CCCN1C(=O)c2ccccc2C1=O)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Yield: 73 %

Procedure:
The compound (6.29 g, 25.75 mmol) obtained in step A was dissolved in N-methylpyrrolidone (100 ml), and the mixture was stirred under ice-cooling. Thereto was added 60% sodium hydride (1.21 g, 30 mmol) and the mixture was stirred at room temperature for 20 min. After stirring, N-(3-bromopropyl)phthalimide (8.31 g, 31.0 mmol) was added and the mixture was stirred at 70° C. for 90 min. The reaction mixture was diluted with ethyl acetate, washed with water, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the solution was concentrated under reduced pressure. The obtained solid was washed with diethyl ether-hexane mixed solvent, and dried under reduced pressure to give the title compound (8.11 g, yield 73%) as a colorless solid.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].[C:10]([O:14][CH2:15][CH3:16])(=[O:13])[CH:11]=[CH2:12]>C1COCC1>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:12][CH2:11][C:10]([O:14][CH2:15][CH3:16])=[O:13])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCNCC1
Reactant: C=CC(=O)OCC
Solvent: C1CCOC1
Product: CCOC(=O)CCN1CCN(C(C)=O)CC1
Temperature: 25 °C
Yield: 50.4 %

Procedure:
A solution of 1-acetylpiperazine (5 g, 39 mmol) in THF (100 mL) was treated with ethyl acrylate (4.2 mL, 39 mmol) then stirred overnight at r.t. after which an additional 4.2 mL of ethyl acrylate was added. The reaction heated at reflux for 5 h, cooled to r.t. and partitioned between dichloromethane and 1N HCl. The acid wash was basified with NaHCO3 to pH 9-10 and extracted 3 times with dichloromethane. Combined organics were dried, filtered and concentrated to give 4.49 g of the title compound as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][N:4]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:3]=1.[CH3:13][N:14]([CH:16]=O)[CH3:15]>CC#N.C(Cl)Cl>[CH3:13][N:14]([CH2:16][C:6]1[C:2]([CH3:1])=[N:3][N:4]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:5]=1)[CH3:15]
Reactant: CCOC(=O)Cn1ccc(C)n1
Reactant: CN(C)C=O
Solvent: CC#N
Solvent: ClCCl
Product: CCOC(=O)Cn1cc(CN(C)C)c(C)n1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 2-(3-methyl-1H-pyrazol-1-yl)acetate (94 mg) and DMF (1.5 mL) in MeCN (3 mL) was added N,N-dimethylmethyleneiminium iodide (390 mg). The reaction mixture was stirred at 90° C. overnight. After cooling down, the reaction mixture was diluted with DCM and washed with sat. NaHCO3 and water. The aq. layers were extracted with DCM, the combined org. layers were dried (MgSO4), filtered off and evaporated in vacuo to afford ethyl 2-(4-((dimethylamino)methyl)-3-methyl-1H-pyrazol-1-yl)acetate (112 mg, brown oil). LC-MS (B): tR=0.39 min; [M+H]+: 226.23.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:10][CH2:9][C@@H:8]([O:11][C:12]2[C:21]3[C:16](=[C:17]([CH3:24])[C:18]([O:22][CH3:23])=[CH:19][CH:20]=3)[N:15]=[C:14]([C:25]3[S:26][CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[N:29]=3)[CH:13]=2)[CH2:7][C@H:6]1[C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35])=[O:4].[Li+].[OH-].Cl>O.C1COCC1>[CH2:37]([O:36][C:34]([C@@H:6]1[CH2:7][C@H:8]([O:11][C:12]2[C:21]3[C:16](=[C:17]([CH3:24])[C:18]([O:22][CH3:23])=[CH:19][CH:20]=3)[N:15]=[C:14]([C:25]3[S:26][CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[N:29]=3)[CH:13]=2)[CH2:9][CH2:10][C@H:5]1[C:3]([OH:4])=[O:2])=[O:35])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: COC(=O)[C@@H]1CC[C@@H](Oc2cc(-c3nc(C(F)(F)F)cs3)nc3c(C)c(OC)ccc23)C[C@H]1C(=O)OCc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2c(O[C@@H]3CC[C@@H](C(=O)O)[C@H](C(=O)OCc4ccccc4)C3)cc(-c3nc(C(F)(F)F)cs3)nc2c1C
Yield: 80 %

Procedure:
A solution of compound 34e (293 mg, 1 eq.) and LiOH (49 mg, 4 eq) in H2O (5 mL) and THF (5 mL) was stirred at room temperature for 4 hrs. The reaction mixture was acidified with 1N HCl to pH 2 and then extracted with DCM. Organics were concentrated under reduced pressure and purified by chromatography on silica gel (DCM/MeOH) to yield compound 34f as beige solid in 80% yield. MS (ESI, EI+): m/z=601 (MH+).