Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([CH2:6][N:7]([CH2:13][CH2:14][C:15]1[S:16][C:17](Br)=[CH:18][CH:19]=1)[C:8](=[O:12])[O:9][CH2:10][CH3:11])=[O:5])C.[OH-].[Na+]>C(O)C>[CH2:10]([O:9][C:8]([N:7]([CH2:6][C:4]([OH:5])=[O:3])[CH2:13][CH2:14][C:15]1[S:16][CH:17]=[CH:18][CH:19]=1)=[O:12])[CH3:11]
Reactant: CCOC(=O)CN(CCc1ccc(Br)s1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)N(CCc1cccs1)CC(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 74 %

Procedure:
To solution of ethyl (ethoxycarbonyl)methyl-2-(5-bromothiophen-2-yl)ethylcarbamate (30.0 g, 105.26 mmol) in ethanol at 0° C. was added dropwise 200 mL of 1N NaOH. The reaction mixture was warmed to RT and stirred for 24 hours. The reaction mixture was extracted with Et2O to remove unreacted starting material and the aqueous layer acidified to pH=1 with 1N HCl. The aqueous solution was extracted with ethyl acetate (2×500 mL) and the combined organics were washed with brine solution, dried (Na2SO4), filtered, and evaporated to obtain crude product. 2-(N-(Ethoxycarbonyl)-N-(2-(thiophen-2-yl)ethyl)amino)acetic acid (74% yield)was obtained as a colorless solid after washing the crude product with pentane; ES-MS: 258.2 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:38]=[CH:37][CH:36]=[CH:35][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:22]=[C:21]3[C:17]([N:18]([CH:24]4[CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25]4)[C:19](=[O:23])[NH:20]3)=[CH:16][N:15]=2)=[N:6]1.[ClH:39]>O1CCOCC1>[ClH:39].[NH:26]1[CH2:25][CH:24]([N:18]2[C:17]3[C:21](=[N:22][C:14]([C:7]4[C:8]5[C:9](=[N:10][CH:11]=[CH:12][CH:13]=5)[N:5]([CH2:4][C:3]5[CH:35]=[CH:36][CH:37]=[CH:38][C:2]=5[F:1])[N:6]=4)=[N:15][CH:16]=3)[NH:20][C:19]2=[O:23])[CH2:27]1
Reactant: CC(C)(C)OC(=O)N1CC(n2c(=O)[nH]c3nc(-c4nn(Cc5ccccc5F)c5ncccc45)ncc32)C1
Agent: Cl
Solvent: C1COCCO1
Product: O=c1[nH]c2nc(-c3nn(Cc4ccccc4F)c4ncccc34)ncc2n1C1CNC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
579 mg (approx. 0.887 mmol, 79% purity) of the compound from example 98A were dissolved 10 ml of dioxane and then admixed with 4 ml of a 4N solution of hydrogen chloride in dioxane and stirred at RT for 0.5 h. This was followed by concentration to dryness. After purification by means of preparative HPLC (acetonitrile:water (+0.05% formic acid) gradient), this gave 168 mg (41% of theory) of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1.[CH:26]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1B(O)O)([CH3:28])[CH3:27]>>[CH:26]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1)([CH3:28])[CH3:27]
Reactant: CC(C)Oc1ccccc1B(O)O
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1Br
Product: CC(C)Oc1ccccc1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 25, from N-(4-bromo-pyridin-3-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamide (example 25, intermediate a) and 2-isopropoxyphenylboronic acid (CAS RN 138008-97-6). Black solid (25%). MS (ESI): m/z=483.0 [M+H]+.
Reaction SMILES: [CH2:1]([NH:4][C:5]([C:7]1[C:15]2[C:10](=[CH:11][C:12]([O:16]C)=[CH:13][CH:14]=2)[N:9]([CH3:18])[C:8]=1[CH3:19])=[O:6])[CH2:2][CH3:3].B(Br)(Br)Br>>[CH2:1]([NH:4][C:5]([C:7]1[C:15]2[C:10](=[CH:11][C:12]([OH:16])=[CH:13][CH:14]=2)[N:9]([CH3:18])[C:8]=1[CH3:19])=[O:6])[CH2:2][CH3:3]
Reactant: CCCNC(=O)c1c(C)n(C)c2cc(OC)ccc12
Agent: BrB(Br)Br
Product: CCCNC(=O)c1c(C)n(C)c2cc(O)ccc12

Procedure:
This material was prepared from 6-methoxy-1,2-dimethyl-1H-indol-3-carboxylic acid propylamide 58a by treatment with BBr3 in a manner as previously described for example 1d. 1H NMR (300 MHz, CD3OD) δ 7.50 (1H, d, J=8.7 Hz), 6.74 (1H, d, J=1.9 Hz), 6.68 (1H, dd, J=1.9, 8.7 Hz), 3.61 (3H, s), 3.32 (2H, m), 2.58 (3H, s), 1.66 (2H, m), 1.01 (3H, t, J=7.4 Hz). LCMS (ESI+) [M+H]/z Calc'd 247. found 247.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[Cl:23][C:24]1[CH:25]=[N:26][C:27]2[N:28]([N:30]=[C:31]([C:33]([OH:35])=O)[CH:32]=2)[CH:29]=1.Cl.[CH3:37][C:38]1[S:39][C:40]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42][C:41]=2[N:47]=1>CN(C=O)C>[Cl:23][C:24]1[CH:25]=[N:26][C:27]2[N:28]([N:30]=[C:31]([C:33]([N:44]3[CH2:45][CH2:46][C:40]4[S:39][C:38]([CH3:37])=[N:47][C:41]=4[CH2:42][CH2:43]3)=[O:35])[CH:32]=2)[CH:29]=1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Reactant: Cc1nc2c(s1)CCNCC2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: Cc1nc2c(s1)CCN(C(=O)c1cc3ncc(Cl)cn3n1)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.72 g (2.23 mmol) TBTU was added to 0.40 g (2.03 mmol) 6-Chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid, 0.41 g (2.03 mmol) 2-Methyl-5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepine hydrochloride and 0.88 mL (6.28 mmol) TEA in 8.0 mL DMF and stirred at RT overnight. The reaction mixture was purified by HPLC chromatography and lyophilized. Yield: 0.18 g (25% of theory). ESI-MS: m/z=348 (M+H)+; Rt(HPLC): 1.01 min. (Method J).
Reaction SMILES: Cl.[Cl:2][C:3]1[N:4]=[C:5]([C:16]2[CH:37]=[CH:36][C:19]([O:20][CH2:21][CH2:22][CH:23]3[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]3)=[C:18]([C:38]([F:41])([F:40])[F:39])[CH:17]=2)[C:6]2[CH:11]=[CH:10][N:9]([CH2:12][CH2:13][O:14][CH3:15])[C:7]=2[N:8]=1>CCOC(C)=O>[ClH:2].[Cl:2][C:3]1[N:4]=[C:5]([C:16]2[CH:37]=[CH:36][C:19]([O:20][CH2:21][CH2:22][CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[C:18]([C:38]([F:39])([F:40])[F:41])[CH:17]=2)[C:6]2[CH:11]=[CH:10][N:9]([CH2:12][CH2:13][O:14][CH3:15])[C:7]=2[N:8]=1
Reactant: COCCn1ccc2c(-c3ccc(OCCC4CCN(C(=O)OC(C)(C)C)CC4)c(C(F)(F)F)c3)nc(Cl)nc21
Agent: Cl
Solvent: CCOC(C)=O
Product: COCCn1ccc2c(-c3ccc(OCCC4CCNCC4)c(C(F)(F)F)c3)nc(Cl)nc21
Reaction time: 1 h
Yield: 199.8 %

Procedure:
A 4 M solution of hydrogen chloride in EtOAc (5 mL) was added to a suspension of tert-butyl 4-(2-{4-[2-chloro-7-(2-methoxyethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-2-(trifluoromethyl)phenoxy}ethyl)piperidine-1-carboxylate (500 mg) in EtOAc (5 mL), and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, whereby 2-chloro-7-(2-methoxyethyl)-4-{4-[2-(piperidin-4-yl)ethoxy]-3-(trifluoromethyl)phenyl}-7H-pyrrolo[2,3-d]pyrimidine monohydrochloride (445 mg) was obtained as a pale yellow solid.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[CH2:6]([NH:9][CH:10]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[O:12][CH2:11]1)[CH2:7][CH3:8]>C(Cl)Cl.[OH-].[Na+]>[C:1]([N:9]([CH:10]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[O:12][CH2:11]1)[CH2:6][CH2:7][CH3:8])(=[O:4])[CH2:2][CH3:3]
Reactant: CCCNC1COc2ccccc2C1
Reactant: CCC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCCN(C(=O)CC)C1COc2ccccc2C1
Reaction time: 0.5 h
Yield: 61.9 %

Procedure:
Propionyl chloride (2.8 g, 29 mmol) was added to a mixture of 15 (1.2 g, 6.4 mmol) in CH2Cl2 and 5% aqueous NaOH. The mixture was stirred for 30 min and separated. The organic layer was extracted with water, separated and dried (MgSO4). The crude product was chromatographed (SiO2) with light petroleum-ether (2:1) as eluant yielding 0.98 g (62%) of 3-(N-propionyl-N-n-propylamino)chroman (16).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][OH:10])[CH:5]=[CH:4][C:3]=1[OH:11].[F:12][C:13]([F:24])([F:23])[C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1>>[F:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][OH:10])[CH:5]=[CH:4][C:3]=1[O:11][C:18]1[CH:17]=[CH:16][CH:15]=[C:14]([C:13]([F:24])([F:23])[F:12])[CH:19]=1
Reactant: OCCc1ccc(O)c(F)c1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Product: OCCc1ccc(Oc2cccc(C(F)(F)F)c2)c(F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D120 starting from 2-fluoro-4-(2-hydroxyethyl)phenol and (3-(trifluoromethyl)phenyl)boronic acid.
Reaction SMILES: [C:1]([CH:3]1[C:12]([C:13]2[CH:14]=[N:15][CH:16]=[C:17]([CH3:19])[CH:18]=2)=[C:11]2[C:6](=[C:7]3[CH:22]=[CH:21][N:20]=[C:8]3[CH:9]=[CH:10]2)[O:5][C:4]1=N)#[N:2].Cl.[OH2:25]>>[C:1]([CH:3]1[C:12]([C:13]2[CH:14]=[N:15][CH:16]=[C:17]([CH3:19])[CH:18]=2)=[C:11]2[C:6](=[C:7]3[CH:22]=[CH:21][N:20]=[C:8]3[CH:9]=[CH:10]2)[O:5][C:4]1=[O:25])#[N:2]
Reactant: O
Reactant: Cc1cncc(C2=c3ccc4c(c3OC(=N)C2C#N)C=CN=4)c1
Agent: Cl
Product: Cc1cncc(C2=c3ccc4c(c3OC(=O)C2C#N)C=CN=4)c1

Procedure:
The process further comprises contacting the 2-iminobenzopyran with an aqueous acid to produce an optionally substituted coumarin (2-oxo-2H-chromene). For example, the hydrolysis of 3-cyano-2-imino-4-(5-methyl-pyridin-3-yl)-2H-pyrrolo[2,3-h]chromene using HCl/H2O produced 3-cyano-4-(5-methyl-pyridin-3-yl)-2-oxo-2H-pyrrolo[2,3-h]chromene (compound of Formula III).
Reaction SMILES: [Na].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].Br[CH2:14][C:15]([C:17]1[C:18]([CH:26]([CH3:28])[CH3:27])=[N:19][N:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=12)=[O:16]>C(O)C>[CH2:11]([O:10][C:2]([CH:3]([CH2:14][C:15]([C:17]1[C:18]([CH:26]([CH3:28])[CH3:27])=[N:19][N:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=12)=[O:16])[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:9])[CH3:12]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(C)c1nn2ccccc2c1C(=O)CBr
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(CC(=O)c1c(C(C)C)nn2ccccc12)C(=O)OCC
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 32.4 %

Procedure:
Sodium (0.10 g) was dissolved into ethanol (4 ml) and diethyl malonate (0.71 g) was added at room temperature. After stirring for 20 minutes at 50° C., a solution of 3-(2-bromoacetyl)-2-isopropylpyrazolo[1,5-a]pyridine (1.06 g) in ethanol (6 ml) was added and the mixture was stirred for 75 minutes at 80° C. The reaction liquor was concentrated, and, water and ethyl acetate were added to the residue to separate the organic layer. After the organic layer was washed with water and with saturated brine and dried over anhydrous sodium sulfate, solvent was distilled off and the residue was purified by means of silica gel column chromatography (developing solvent, ethyl acetate, n-hexane=1:3) to obtain aimed product (0.44 g) as pale yellow powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([CH:13]([CH2:19][NH2:20])[CH2:14][CH2:15][N:16]([CH3:18])[CH3:17])[N:12]=2)=[CH:4][CH:3]=1.[F:21][C:22]([F:38])([F:37])[C:23]1[O:27][N:26]=[C:25]([C:28]2[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=2)[C:31](O)=[O:32])[N:24]=1>>[CH3:17][N:16]([CH3:18])[CH2:15][CH2:14][CH:13]([C:11]1[N:12]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[O:9][CH:10]=1)[CH2:19][NH:20][C:31](=[O:32])[C:30]1[CH:34]=[CH:35][CH:36]=[C:28]([C:25]2[N:24]=[C:23]([C:22]([F:38])([F:37])[F:21])[O:27][N:26]=2)[CH:29]=1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: CN(C)CCC(CN)c1coc(-c2ccc(F)cc2)n1
Product: CN(C)CCC(CNC(=O)c1cccc(-c2noc(C(F)(F)F)n2)c1)c1coc(-c2ccc(F)cc2)n1
Yield: 10 %

Procedure:
This compound was synthesized from 3-(2-(4-fluorophenyl)oxazol-4-yl)-N1,N1-dimethylbutane-1,4-diamine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (17 mg, yield 10%). 1H NMR (400 MHz, MeOD) δ 8.55-8.54 (t, J=1.5 Hz, 1H), 8.30-8.27 (m, 1H), 8.08-8.02 (m, 3H), 7.82 (s, 1H), 7.71-7.67 (t, J=7.8 Hz, 1H), 7.26-7.21 (t, J=8.9 Hz, 2H), 3.76-3.65 (m, 2H), 3.16-3.10 (m, 1H), 2.53-2.40 (m, 2H), 2.30 (m, 6H), 2.04-1.98 (m, 2H). MS (ESI) m/z: Calculated for C24H22F4N6O3: 518.17. found: 519.2 (M+H)+.
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[OH:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>>[C:1]([N:17]1[CH2:18][CH2:19][CH:14]([OH:13])[CH2:15][CH2:16]1)(=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCC/C=C/C(=O)O
Reactant: OC1CCNCC1
Product: CCCCCCC/C=C/C(=O)N1CCC(O)CC1

Procedure:
The same procedures as in Example 2 were carried out using (E)-2-decenoic acid and 4-hydroxypiperidine as starting raw materials, to produce an intended compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:12]2[CH2:16][O:15][C:14]([CH3:18])([CH3:17])[O:13]2)[C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:12]2[CH2:16][O:15][C:14]([CH3:18])([CH3:17])[O:13]2)[CH2:10][NH2:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC1(C)OCC(C(C#N)c2ccc(Cl)c(Cl)c2)O1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: CC1(C)OCC(C(CN)c2ccc(Cl)c(Cl)c2)O1
Reaction time: 3 h
Yield: 100.6 %

Procedure:
To a solution of (2RS)-(3,4-dichlorophenyl)[(4RS)-2,2-dimethyl-1,3-dioxolan-4-yl]ethanenitrile (10.0 g) in toluene (100 ml) was added dropwise 1.5 M diisobutylaluminum hydride/toluene solution (51.3 under nitrogen purging at −78° C., and the mixture was stirred for 3 hr. The reaction was quenched with water at −78° C., aqueous potassium carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated to give the title compound (10.2 g) as a colorless oil. This was used for the next step without purification.
Reaction SMILES: FC(F)(F)C(O)=O.CS(O)(=O)=O.C(O[C:16]([C:31]1[CH:35]=[C:34]([N:36]=[C:37]([NH2:44])[N:38]2[CH2:43][CH2:42][O:41][CH2:40][CH2:39]2)[O:33][N:32]=1)([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:20]([F:30])[CH:19]=1)[CH3:17])C.[Cl-].[Na+]>C(Cl)Cl>[F:30][C:20]1[CH:19]=[C:18]([C:16]([C:31]2[CH:35]=[C:34]([N:36]=[C:37]([NH2:44])[N:38]3[CH2:39][CH2:40][O:41][CH2:42][CH2:43]3)[O:33][N:32]=2)=[CH2:17])[CH:23]=[CH:22][C:21]=1[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCOC(C)(c1ccc(-c2ccccc2)c(F)c1)c1cc(N=C(N)N2CCOCC2)on1
Agent: CS(=O)(=O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=C(c1ccc(-c2ccccc2)c(F)c1)c1cc(N=C(N)N2CCOCC2)on1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.8 %

Procedure:
Trifluoroacetic acid (4 ml) was added to a solution of the compound (30.0 mg) obtained in Example 53 in methylene chloride (1 ml), and the resulting mixture was stirred at room temperature for 8 hours. After the addition of a saturated aqueous sodium chloride solution, the mixture was subjected to extraction with ethyl acetate, and the organic layer was washed successively with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, thereafter dried over sodium sulfate and then concentrated under reduced pressure. The residue was purified by a silica gel column chromatography to obtain the desired compound (20 mg).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:9]([N:10]2[C:14]3[CH:15]=[C:16]([Cl:20])[C:17]([Cl:19])=[CH:18][C:13]=3[N:12]=[CH:11]2)[CH2:8][C@@H:7]([CH2:21][O:22][C:23](=[O:25])[CH3:24])[C@@H:6]1[O:26][C:27](=[O:29])[CH3:28])(=[O:3])[CH3:2].[Cl:30]N1C(=O)CCC1=O>CN(C)C=O>[C:1]([O:4][C@@H:5]1[C@@H:9]([N:10]2[C:14]3[CH:15]=[C:16]([Cl:20])[C:17]([Cl:19])=[CH:18][C:13]=3[N:12]=[C:11]2[Cl:30])[CH2:8][C@@H:7]([CH2:21][O:22][C:23](=[O:25])[CH3:24])[C@@H:6]1[O:26][C:27](=[O:29])[CH3:28])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@@H]1C[C@H](n2cnc3cc(Cl)c(Cl)cc32)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: CC(=O)OC[C@@H]1C[C@H](n2c(Cl)nc3cc(Cl)c(Cl)cc32)[C@@H](OC(C)=O)[C@H]1OC(C)=O

Procedure:
(±)-(1R*,2S*,3S*,5S*)-3-(Acetoxymethyl)-5-(5,6-dichloro-1H-benzimidazol-1-yl)-1,2-cyclopentanediyl diacetate (850 mg, 1.92 mmol) in dry N,N-dimethylformamide (5 mL) was maintained at 95° C. while N-chlorosuccinimide (760 mg) was added in portions over 3 hours. Heating was continued for a total of 6 hours. Volatiles were removed in vacuo and the residue chromatographed on silica gel. Title compound was eluted with ethyl acetate:hexanes/3:7 as a yellow solid (160 mg, 17%), 1H-NMR consistent with structure and almost identical with that of title compound of Example 3.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([N:12]2[C:13]([CH3:17])([CH3:16])[C:14](=[O:15])[N:11]2[CH:2]2[CH:3]3[CH2:4][CH:5]4[CH2:6][CH:7]([CH2:8][CH:1]2[CH2:10]4)[CH2:9]3)(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1S(=O)(=O)c1ccc(Cl)cc1

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one prepared in Process 5 of Example 12 and 4-chlorobenzene sulfonyl chloride were used for a similar reaction and treatment as Example 169, and the title compound was obtained as a colorless crystalline powder.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[N:10]1[CH2:15][CH2:14][CH:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:12][CH2:11]1)([O-])=O.I[CH3:25].[H-].[Na+]>CN(C=O)C.CO.[Pd]>[NH2:1][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[N:10]1[CH2:15][CH2:14][CH:13]([N:16]([CH3:25])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:12][CH2:11]1
Reactant: CI
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccncc2[N+](=O)[O-])CC1
Agent: [Pd]
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)C1CCN(c2ccncc2N)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl N-[1-(3-nitro-4-pyridyl)-4-piperidyl]carbamate (2100 mg, 6.514 mmol) (prepared according to methods similar to the one depicted in Step 1 of Preparation N-1) and iodomethane (4.623 g, 2.028 mL, 32.57 mmol) in DMF at 0° C. was added portionwise sodium hydride (312.7 mg, 7.817 mmol). The reaction was stirred at 0° C. for 1 h, and at room temperature for 1 h. The reaction was quenched by pouring the reaction mixture onto a saturated aqueous solution of ammonium chloride, then extracted with ethyl acetate (2×50 mL). The combined organics was washed with brine (2×50 mL), dried and evaporated to leave an orange solid. To the crude solid dissolved in MeOH (50 mL) was added Pd/C (10%) (346 mg) and the mixture was stirred under a hydrogen atmosphere for 4 h. The reaction was filtered through celite and evaporated to leave tert-butyl (1-(3-aminopyridin-4-yl)piperidin-4-yl)(methyl)carbamate as a yellow oil. (600 mg, 20%) MS (ES+-tBu) 251.1.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([CH2:7][S:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)=[N:5][N:6]=1>C(O)(=O)C>[CH3:1][C:2]1[O:3][C:4]([CH2:7][S:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)=[N:5][N:6]=1
Reactant: Cc1nnc(CSc2ccc([N+](=O)[O-])cc2)o1
Solvent: CC(=O)O
Product: Cc1nnc(CSc2ccc(N)cc2)o1
Temperature: 25 °C
Reaction time: 240 h
Yield: 75.7 %

Procedure:
To 2-methyl-5-[[(4-nitrophenyl)sulfanyl]methyl]-1,3,4-oxadiazole (3.3 g) was added acetic acid (33 ml), and reduced iron (9.9 g) was added to the mixture, and the mixture was stirred for 240 hours at room temperature. The mixture was filtered with Celite, and the mixture was washed with ethyl acetate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 4-[[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]sulfanyl]aniline (2.2 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[N:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[C:4]=1[C:5]([O:7]C)=[O:6].[OH-].[Na+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[N:14]=[CH:15][CH:16]=[CH:17][N:18]=2)[C:4]=1[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1c(OC)cccc1-c1ncccn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cccc(-c2ncccn2)c1C(=O)O
Temperature: 50 °C

Procedure:
To a solution of the title compound of Step A (265 mg, 1.09 mmol) in THF (4 mL) was added 2 N NaOH (2 mL). The mixture was heated at 50° C. for 72 h. The reaction mixture was concentrated in vacuo to a white solid which was used without further purification in subsequent steps. MS (ESI) mass calcd. for C12H10N2O3, 230.1; m/z found 231.1 [M+H]+. 1H NMR (500 MHz, DMSO-d6) 12.63 (s, 1H), 8.86 (d, J=4.9 Hz, 2H), 7.77 (dd, J=7.9, 1.0 Hz, 1H), 7.51 (t, J=8.1 Hz, 1H), 7.45 (t, J=4.9 Hz, 1H), 7.25 (dd, J=8.4, 1.0 Hz, 1H), 3.83 (s, 3H).
Reaction SMILES: [NH2:1][C:2](=[O:38])[CH:3]([OH:37])[CH:4]([NH:12][C:13](=[O:36])[C:14]1[CH:19]=[CH:18][CH:17]=[N:16][C:15]=1[N:20]1[CH:35]=[C:23]2[N:24]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:25][CH2:26][CH2:27][C:22]2=[N:21]1)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>ClCCl.CO>[NH2:1][C:2](=[O:38])[C:3](=[O:37])[CH:4]([NH:12][C:13](=[O:36])[C:14]1[CH:19]=[CH:18][CH:17]=[N:16][C:15]=1[N:20]1[CH:35]=[C:23]2[N:24]([CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:25][CH2:26][CH2:27][C:22]2=[N:21]1)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NC(=O)C(O)C(Cc1ccccc1)NC(=O)c1cccnc1-n1cc2c(n1)CCCN2Cc1ccccc1
Solvent: ClCCl
Solvent: CO
Product: NC(=O)C(=O)C(Cc1ccccc1)NC(=O)c1cccnc1-n1cc2c(n1)CCCN2Cc1ccccc1

Procedure:
Oxidation of N-(4-amino-3-hydroxy-4-oxo-1-phenylbutan-2-yl)-2-(4-benzyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-b]pyridin-2-yl)nicotinamide (150 mg, 0.294 mmol) as described in example 2.4 and purification by chromatography over silica gel (eluent: dichloromethane/methanol) afforded the title compound as an amorpous solid; 11 mg, ESI-MS [M+H]+: 509.2. 1H-NMR (400 MHz, DMSO), δ[ppm]: 8.62 (m, 1H), 8.35 (m, 2H), 7.76 (m, 1H), 7.50 (m, 1H), 7.35-7.12 (m, 12H), 5.85 (s, 1H), 4.36 (m, 1H), 4.20 (s, 2H), 3.20 (m, 2H), 2.93 (m, 2H), 2.71 (m, 3H), 1.94 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]([N:12]2[CH2:17][CH2:16][O:15][C:14]3[CH:18]=[CH:19][N:20]=[CH:21][C:13]2=3)=[O:11])[CH:5]=[CH:6][C:7]=1[O:8]C.B(Br)(Br)Br>ClCCl.CCCCCC>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]([N:12]2[CH2:17][CH2:16][O:15][C:14]3[CH:18]=[CH:19][N:20]=[CH:21][C:13]2=3)=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: COc1ccc(C(=O)N2CCOc3ccncc32)cc1Cl
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CCCCCC
Product: O=C(c1ccc(O)c(Cl)c1)N1CCOc2ccncc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 37.7 %

Procedure:
In a 25 ml flask, (3-chloro-4-methoxy-phenyl)-(2,3-dihydro-pyrido[4,3-b][1,4]oxazin-4-yl)-methanone (223 mg, 0.73 mmol) was dissolved in dichloromethane, and the mixture was cooled to 0□. 1.0M Boron tribromide dissolved in dichloromethane (3.65 ml, 3.65 mmol) was added thereto and stirred at room temperature for 16 hours. n-hexane solvent was added thereto and the formed solid was filtered. The resulting solid was dissolved in methanol and concentrated. After adding and dissolving in water, the mixture was adjusted to pH 6 with saturated solution of sodium hydrogen carbonate and then extracted with dichloromethane. The combined organic layer was dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was recrystallized from dichloromethane and n-hexane to obtain the target compound 37 as white solid (80 mg, 38%).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]([C:15](=[O:17])[CH3:16])[CH:12]=[CH:13][CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Br-:18].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(OCC)C>[Br:18][CH2:16][C:15]([C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH:10]=1)=[O:17]
Reactant: CC(=O)c1cccc(O[Si](C)(C)C(C)(C)C)c1
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)Oc1cccc(C(=O)CBr)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution (40 mL) of the compound (9.4 g, 37 mmol) obtained in Example 38a in diethyl ether was added phenyltrimethylammonium tribromide (14 g, 37 mmol), and the mixture was stirred at room temperature for 5 hr. After confirmation of the termination of the reaction by TLC, aqueous sodium thiosulfate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give a crude title compound as a colorless oil.