Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:9][O:8][B:7]([OH:10])[C:6]=2[CH:11]=1.CN1CCOCC1.[CH3:19][S:20]([CH2:22][CH2:23][C:24]1[CH:29]=[C:28]([NH:30][C:31](=[O:36])[C:32]([F:35])([F:34])[F:33])[CH:27]=[CH:26][C:25]=1[S:37](Cl)(=[O:39])=[O:38])=[O:21]>CC#N>[F:34][C:32]([F:33])([F:35])[C:31]([NH:30][C:28]1[CH:27]=[CH:26][C:25]([S:37](=[O:38])(=[O:39])[NH:1][C:2]2[CH:3]=[CH:4][C:5]3[CH2:9][O:8][B:7]([OH:10])[C:6]=3[CH:11]=2)=[C:24]([CH2:23][CH2:22][S:20]([CH3:19])=[O:21])[CH:29]=1)=[O:36]
Reactant: CS(=O)CCc1cc(NC(=O)C(F)(F)F)ccc1S(=O)(=O)Cl
Reactant: Nc1ccc2c(c1)B(O)OC2
Solvent: CN1CCOCC1
Solvent: CC#N
Product: CS(=O)CCc1cc(NC(=O)C(F)(F)F)ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.5 %

Procedure:
To a solution of 6-amino-3H-benzo[c][1,2]oxaborol-1-ol (0.59 g, 3.9 mmol) and N-methylmorpholine (2.53 g, 25 mmol) in MeCN (70 mL) was added 2-(2-(methylsulfinyl)ethyl)-4-(2,2,2-trifluoroacetamido)benzene-1-sulfonyl chloride (1 g, crude, 2.6 mmol) in MeCN (20 mL) at 0° C., then the solution was stirred at room temperature overnight. The mixture was concentrated in vacuo, and ethyl acetate and water was added to the residue. The organic layer was dried over Na2SO4 and concentrated to give the crude product. The residue was purified by prep-HPLC (column: Luna 300×50.0 mm, 10 um; liquid phase: [A-H2O+0.05% TFA; B-MeCN] B %: 30%-60%, 25 min) to give 2,2,2-trifluoro-N-(4-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)-3-(2-(methylsulfinyl)ethyl)phenyl)acetamide (0.3 g, yield 32%).
Reaction SMILES: [O:1]=[C:2]1[CH2:8][CH:7]2[N:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:4]([CH2:5][CH2:6]2)[CH2:3]1.[BH4-].[Na+]>C(O)C.ClCCl>[OH:1][CH:2]1[CH2:3][CH:4]2[N:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:7]([CH2:6][CH2:5]2)[CH2:8]1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(=O)C2
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C2CCC1CC(O)C2
Reaction time: 3 h
Yield: 93.6 %

Procedure:
3-Oxo-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid, tert-butyl ester (8 g, 35.5 mmol) was dissolved in 100 mL of ethanol. Sodium borohydride (2 g, 53.5 mmol) was added to the solution portionwise at room temperature. After stirring for 3 hours, the reaction was evaporated in vacuo to give clear viscous oil. The oil was dissolved in dichloromethane, washed with water and brine, dried over anhydrous sodium sulfate, filtered, and evaporated to afford 7.55 g of 3-hydroxy-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid, tert-butyl ester as a white crystalline solid; 1H NMR (300 MHz, DMSO-d6): 4.23 (dd, J=2.7, 4.6 Hz, 1H), 4.18-4.06 (m, 2H), 2.17-2.06 (m, 1H), 1.99-1.91 (m, 3H), 1.72-1.50 (m, 5H), 1.47 (s, 9H).
Reaction SMILES: [S:1]1C=C[CH:3]=[C:2]1CC(O)=O.[C:10]([O:18][C:19]([NH:21][CH2:22][CH2:23][CH2:24][CH:25](Br)[C:26]([OH:28])=[O:27])=[O:20])(=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[OH2:30]>C(=O)([O-])[O-].[K+].[K+]>[C:2]([S:1][CH:25]([CH2:24][CH2:23][CH2:22][NH:21][C:19]([O:18][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:20])[C:26]([OH:28])=[O:27])(=[O:30])[CH3:3]
Reactant: O=C(O)Cc1cccs1
Reactant: O=C(NCCCC(Br)C(=O)O)OC(=O)c1ccccc1
Reactant: O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(=O)SC(CCCNC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Thiolacetic acid (1 g.) is added to a solution of 5-benzoyloxycarbonylamino-2-bromopentanoic acid [Chem. Pharm. Bull., 24, 326 (1976)] (3.3 g.) in a mixture of water (30 ml.) and potassium carbonate (1.38 g.). The mixture is stirred at room temperature overnight, acidified and extracted with ethyl acetate to yield 2-acetylthio-5-benzyloxycarbonylaminopentanoic acid.
Reaction SMILES: Br[C:2]1[CH:6]=[C:5]([Si](C)(C)C)[S:4][C:3]=1[C:11]1[S:12][C:13]([Si](C)(C)C)=[CH:14][C:15]=1Br.C([Li])CCC.[CH3:26][CH:27]([CH2:43][CH2:44][CH2:45][CH:46]([CH3:48])[CH3:47])[CH2:28][CH2:29][Si:30]([CH2:33][CH2:34][CH:35]([CH3:42])[CH2:36][CH2:37][CH2:38][CH:39]([CH3:41])[CH3:40])(Cl)Cl.O>O1CCCC1.CCCCCC>[CH3:26][CH:27]([CH2:43][CH2:44][CH2:45][CH:46]([CH3:48])[CH3:47])[CH2:28][CH2:29][Si:30]1([CH2:33][CH2:34][CH:35]([CH3:42])[CH2:36][CH2:37][CH2:38][CH:39]([CH3:40])[CH3:41])[C:2]2[CH:6]=[CH:5][S:4][C:3]=2[C:11]2[S:12][CH:13]=[CH:14][C:15]1=2
Reactant: CC(C)CCCC(C)CC[Si](Cl)(Cl)CCC(C)CCCC(C)C
Reactant: C[Si](C)(C)c1cc(Br)c(-c2sc([Si](C)(C)C)cc2Br)s1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: CC(C)CCCC(C)CC[Si]1(CCC(C)CCCC(C)C)c2ccsc2-c2sccc21
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 56 %

Procedure:
3,3′-dibromo-5,5′-bis(trimethylsilyl)-2,2′-bithiophene (Compound G4, synthesized in accordance with WO 2010/136353, 11.6 g, 24.7 mmol) was placed in a 500 mL four-necked flask in a nitrogen atmosphere, and dissolved in tetrahydrofuran (200 mL). This was cooled to −78° C., and a solution of n-butyl lithium in hexane (KANTO CHEMICAL CO., INC., 1.59 M, 32.7 mL) was added dropwise. After about 20 minutes of agitation, the bis(3,7-dimethyloctyl)dichlorosilane (Compound G21, 11.3 g) synthesized in Synthesis Example B18 was added dropwise. The temperature was raised gradually to room temperature over the course of about 2 hours, water was added, and the product was extracted with hexane. The organic layer was washed with water, dried over sodium sulfate, and concentrated by filtration. The resulting oily substance was dissolved in chloroform (40 mL) and hexane (80 mL), trifluoroacetic acid (3.7 mL) was added, and the mixture was agitated for about 10 minutes at room temperature. Saturated sodium bicarbonate solution was added to the reaction solution, which was extracted with hexane and then concentrated under reduced pressure. The resulting yellow oily substance was dissolved in hexane, and subjected to silica gel column chromatography (solvent: hexane) to obtain the target 4,4-bis(3,7-dimethyloctyl)-dithieno[3,2-b:2′,3′-d]silole (Compound G22, 6.5 g, yield 56%.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[CH2:3][CH2:4][CH2:5][N:6]1[CH2:22][CH2:21][C:9]2[NH:10][C:11]3[C:16]([C:8]=2[CH2:7]1)=[C:15]1[C:17]([CH3:20])=[CH:18][S:19][C:14]1=[CH:13][CH:12]=3.[H-].[Na+].[CH3:26][N:27]([CH3:32])[CH2:28][CH2:29][CH2:30]Cl.[C:33]([O-:40])(=[O:39])/[CH:34]=[CH:35]\[C:36]([O-:38])=[O:37]>>[C:33]([OH:40])(=[O:39])/[CH:34]=[CH:35]\[C:36]([OH:38])=[O:37].[C:33]([OH:40])(=[O:39])/[CH:34]=[CH:35]\[C:36]([OH:38])=[O:37].[C:33]([OH:40])(=[O:39])/[CH:34]=[CH:35]\[C:36]([OH:38])=[O:37].[CH3:26][N:27]([CH3:32])[CH2:28][CH2:29][CH2:30][N:10]1[C:11]2[C:16](=[C:15]3[C:17]([CH3:20])=[CH:18][S:19][C:14]3=[CH:13][CH:12]=2)[C:8]2[CH2:7][N:6]([CH2:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:23])[CH2:22][CH2:21][C:9]1=2
Reactant: O=C([O-])/C=C\C(=O)[O-]
Reactant: CN(C)CCCCl
Reactant: Cc1csc2ccc3[nH]c4c(c3c12)CN(CCCN(C)C)CC4
Agent: [H-]
Agent: [Na+]
Product: Cc1csc2ccc3c(c4c(n3CCCN(C)C)CCN(CCCN(C)C)C4)c12
Product: O=C(O)/C=C\C(=O)O

Procedure:
The compound is formed analogously to that described in Example 31, from 5 g of 9-(3-dimethylaminopropyl)-1-methyl-7,8,9,10-tetrahydrothieno[3,2-e]pyrido[4,3-b]indole, NaH and 3-dimethylaminopropyl chloride indimethylformamide, the product subsequently being converted into the maleate. Melting point: 174° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH2:16]([O:18][C:19]([N:21]=[C:22]=[S:23])=[O:20])[CH3:17]>>[C:1]([O:5][C:6](=[O:15])[NH:7][C@H:8]1[CH2:9][CH2:10][C@H:11]([NH:14][C:22]([NH:21][C:19]([O:18][CH2:16][CH3:17])=[O:20])=[S:23])[CH2:12][CH2:13]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCC(N)CC1
Reactant: CCOC(=O)N=C=S
Product: CCOC(=O)NC(=S)N[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C

Procedure:
To a solution of 1.10 g of (4-amino-cyclohexyl)-carbamic acid tert-butyl ester in 25 ml of EtAc 0.58 ml of ethoxycarbonyl-isothiocyanat are added and the mixture obtained is stirred at RT. The precipitate formed is filtered and washed with diethylether. [trans-4-(3-Ethoxycarbonyl-thioureido)cyclohexyl]carbamic acid tert-butyl ester is obtained.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([CH3:13])[C:11]=1[OH:12])[C:6]([OH:8])=[O:7])=O.C([O-])([O-])=O.[K+].[K+].C(N(CC)CC)C.[F:27][C:28]([F:37])([F:36])/[CH:29]=[CH:30]/[C:31]([O:33][CH2:34][CH3:35])=[O:32].Cl>CS(C)=O.CC(C)=O>[CH2:34]([O:33][C:31]([C:30]1[CH:29]([C:28]([F:27])([F:36])[F:37])[O:12][C:11]2[C:3]([CH:1]=1)=[CH:4][C:5]([C:6]([OH:8])=[O:7])=[CH:9][C:10]=2[CH3:13])=[O:32])[CH3:35]
Reactant: Cc1cc(C(=O)O)cc(C=O)c1O
Reactant: CCOC(=O)/C=C/C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CCOC(=O)C1=Cc2cc(C(=O)O)cc(C)c2OC1C(F)(F)F
Temperature: 90 °C

Procedure:
A mixture of 3-formyl-4-hydroxy-5-methylbenzoic acid (8.8 g, 48.89 mmole), K2CO3 (13.49 g, 97.78 mmole), triethylamine (19.79 g, 195.56 mmole), and ethyl 4,4,4-trifluorocrotonate (32.85 g, 195.56 mmole) in anhydrous DMSO (20.0 mL) was heated to 90° C. under a dry N2 atmosphere for 18 hrs. The mixture was then cooled, poured into 2.0 N HCl (100 ml), and extracted with EtOAc (2×100 mL). The combined extracts were washed with brine (100 mL), dried over MgSO4, filtered, and concentrated in vacuo to give an oily solid. Redissolved in acetone to givea white precipitat, which was filtered and dried on high vacuum (7.2 g, 51%). GCMS m/z 330.0 (M+). 1H NMR (DMSO/400 MHz) 12.99 (s, 1H), 8.11 (s, 1H), 8.06 (s, 1H), 7.94 (s, 1H), 6.19 (q, 1H, J=7.0 Hz), 4.35 (m, 2H), 2.31 (s, 3H), 1.36 (m, 3H).
Reaction SMILES: CC(C)(S([NH:6][C:7]1([C:18]2[N:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8]1)=O)C.[ClH:25].CCOCC>CO>[ClH:25].[NH2:6][C:7]1([C:18]2[N:19]=[CH:20][CH:21]=[CH:22][N:23]=2)[CH2:8][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CC(NS(=O)C(C)(C)C)(c2ncccn2)C1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC(N)(c2ncccn2)C1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 87 %

Procedure:
tert-Butyl 3-(1,1-dimethylethylsulfinamido)-3-(pyrimidin-2-yl)azetidine-1-carboxylate (40 mg, 0.113 mmol) in MeOH (0.5 ml) in a 10 ml round-bottomed flask was cooled to 0° C. A solution of HCl in ether (0.141 ml, 0.564 mmol, 4 N) was added. The mixture was then stirred at 0° C. for 15 min and then concentrated at room temperature. The residue was triturated with hexane and diethyl ether. The resulting solid was allowed to settle and supernatant liquid was decanted. The solid obtained was dried under vacuo to afford tert-butyl 3-amino-3-(pyrimidin-2-yl)azetidine-1-carboxylate hydrochloride Yield: 28 mg (87%). 1H NMR (400 MHz, DMSO-d6): δ 9.08 (bs, 2H), 9.0 (d, J=4.8 Hz, 2H), 7.63 (t, J=4.8 Hz, 1H), 4.23-4.21 (m, 4H), 1.43 (s, 9H). LCMS: (ES+) m/z observed=151.2 (M+H)+ of 3-(pyrimidin-2-yl)azetidin-3-amine
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[C:21]([F:24])([F:23])[F:22])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.ClC(Cl)C>ClCCl>[F:20][C:17]1[CH:18]=[CH:19][C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[C:15]([C:21]([F:22])([F:24])[F:23])[CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(F)cc2C(F)(F)F)CC1
Solvent: ClCCl
Solvent: CC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: Fc1ccc(N2CCNCC2)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 79.9 %

Procedure:
To a stirred solution of tert-butyl-4-(4-fluoro-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate (6.8 g, 19.5 mmol) in anhydrous dichloromethane (90 mL) was added TFA (45 mL) dropwise at 0° C. The reaction mixture was stirred at 0° C. for 15 minutes then the cooling bath was removed and it was allowed to stir at room temperature for 2 hours. Reaction was complete as determined by TLC. Most of TFA was azeotropped with dichloroethane. The residue was then diluted with dichloromethane and washed with saturated Na2CO3 (aq.). Organic layer was dried over MgSO4. Solvent evaporation afforded 1-(4-fluoro-2-(trifluoromethyl)phenyl)piperazine in 79.9% yield (3.86 g) as light brown oil. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 2.78-2.90 (m, 4H) 2.96-3.04 (m, 4H) 7.18-7.25 (m, 1H) 7.29-7.42 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6](O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].ClC[C:13]1[O:17][C:16]([C:18]([O:20][CH3:21])=[O:19])=[CH:15][CH:14]=1.[C:22]([O-])([O-])=[O:23].[K+].[K+]>CC(C)=O.O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:23][CH2:22][C:14]2[CH:15]=[C:16]([C:18]([O:20][CH3:21])=[O:19])[O:17][CH:13]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: COC(=O)c1ccc(CCl)o1
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)c1cc(COc2ccc([N+](=O)[O-])cc2)co1
Yield: 90.8 %

Procedure:
3-Nitrophenol (1.0 g, 7.19 mmole), methyl 5-(chloromethyl)-2-furoate (1.38 g, 7.90 mmole) and anhydrous K2CO3 (1.19 g, 8.60 mmole) in acetone (30 mL) were refluxed for 8 h. The reaction mixture was cooled and diluted with water. The resultant white solid was filtered, washed with water and air dried overnight to give 1.81 g (90%) of the desired product. 1H NMR (CDCl3): δ 7.86 (dd, 1H, J=2.3 and 8.2 Hz), 7.80 (t, 1H, J=2.3 Hz), 7.45 (t, 1H, J=8.2 Hz), 7.27 (dd, 1H, J=2.3 and 8.2 Hz), 7.17 (d, 1H, J=3.5 Hz), 6.58 (d, 1H, J=3.5 Hz), 5.13 (s, 2H), 3.90 (s, 3H).
Reaction SMILES: [CH:1]([C:3]1[C:4]([C:27]([F:30])([F:29])[F:28])=[N:5][N:6]([CH2:8][C:9]([NH:11][C:12]2[S:16][C:15]3[CH2:17][CH2:18][CH2:19][CH2:20][C:14]=3[C:13]=2[C:21]([NH:23][CH2:24][CH2:25][OH:26])=[O:22])=[O:10])[CH:7]=1)=O.[F:31][C:32]([F:36])([F:35])[CH2:33][NH2:34].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.C(Cl)Cl>[OH:26][CH2:25][CH2:24][NH:23][C:21]([C:13]1[C:14]2[CH2:20][CH2:19][CH2:18][CH2:17][C:15]=2[S:16][C:12]=1[NH:11][C:9](=[O:10])[CH2:8][N:6]1[CH:7]=[C:3]([CH2:1][NH:34][CH2:33][C:32]([F:36])([F:35])[F:31])[C:4]([C:27]([F:29])([F:30])[F:28])=[N:5]1)=[O:22]
Reactant: O=Cc1cn(CC(=O)Nc2sc3c(c2C(=O)NCCO)CCCC3)nc1C(F)(F)F
Reactant: NCC(F)(F)F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C(Cn1cc(CNCC(F)(F)F)c(C(F)(F)F)n1)Nc1sc2c(c1C(=O)NCCO)CCCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.4 %

Procedure:
2-(2-(4-Formyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamido)-N-(2-hydroxyethyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (30 mg, 0.068 mmol), 2,2,2-trifluoroethylamine (19.8 mg, 0.20 mmol) and DCM (1 mL) were treated with acetic acid (5 drops) and sodium triacetoxyborohydride (58 mg, 0.272 mmol) and the mixture stirred at RT overnight. The sample was concentrated and re-dissolved in dimethylsulfoxide (1 mL), filtered and purified by preparative LCMS followed by additional purification by SCX ion exchange chromatography to yield the title compound (10 mg, 0.02 mmol, 29%).
Reaction SMILES: [F:1][C:2]1[C:3]([OH:12])=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].P([O-])(O)(O)=[O:14].[Na+].Cl([O-])=O.[Na+]>CS(C)=O.O>[F:1][C:2]1[C:3]([OH:12])=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[C:5]([OH:14])=[O:6]
Reactant: COc1ccc(C=O)c(O)c1F
Reactant: O=P([O-])(O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(C(=O)O)c(O)c1F
Temperature: 20 °C
Reaction time: 16 h
Yield: 67.8 %

Procedure:
To a mixture of 3-fluoro-2-hydroxy-4-methoxybenzaldehyde (10.0 g) and sodium dihydrogenphosphate (22.9 g) in DMSO (100 mL) and water (25.0 mL) was added dropwise an aqueous solution (30.0 mL) of sodium chlorite (14.5 g), and the mixture was stirred at 20° C. for 16 hr. The solvent was evaporated under reduced pressure, the residue was diluted with water, and the mixture was extracted with ethyl acetate (×6). The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (7.42 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:25])=[C:6]([N:8]2[C:12]([C:13]([O:15]CC)=[O:14])=[CH:11][C:10]([C:18](=O)/[CH:19]=[CH:20]/N(C)C)=[N:9]2)[CH:7]=1.C(=O)(O)O.[NH2:30][C:31]([NH2:33])=[NH:32]>CN(C=O)C>[NH2:32][C:31]1[N:33]=[C:18]([C:10]2[CH:11]=[C:12]([C:13]([OH:15])=[O:14])[N:8]([C:6]3[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[CH3:25])[N:9]=2)[CH:19]=[CH:20][N:30]=1
Reactant: CCOC(=O)c1cc(C(=O)/C=C/N(C)C)nn1-c1cc(Cl)ccc1C
Reactant: N=C(N)N
Agent: O=C(O)O
Solvent: CN(C)C=O
Product: Cc1ccc(Cl)cc1-n1nc(-c2ccnc(N)n2)cc1C(=O)O
Temperature: 110 °C
Yield: 65.7 %

Procedure:
To a mixture of ethyl 1-(5-chloro-2-methylphenyl)-3-[(2E)-3-(dimethylamino)prop-2-enoyl]-1H-pyrazole-5-carboxylate (260 mg, 0.72 mmol) in DMF (4 mL), guanidine carbonate (130 mg, 0.72 mmol) was added. The mixture was heated at 110° C. overnight under efficient stirring. The resulting mixture was concentrated, dissolved in MeOH (0.5 mL) and THF (0.5 mL) and treated with NaOH 1N (0.5 mL). After 1 h the mixture was concentrated, dissolved in water and washed with AcOEt. To the aqueous phase cooled to 5° C., a saturated solution of citric acid was added under stirring. The resulting precipitate was collected by filtration to give the title compound (156 mg, 65%).
Reaction SMILES: FC1C=C(C=CC=1OCCN1CCCCC1)CNC1C=CC=CC=1C1CCC2C(=CC=C(OC)C=2)C1.[CH2:37]([N:39]([CH2:58][C:59]1[CH:64]=[CH:63][C:62]([O:65][CH2:66][CH2:67][N:68]2[CH2:73][CH2:72][CH2:71][CH2:70][CH2:69]2)=[C:61]([F:74])[CH:60]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[CH:46]1[CH2:55][CH2:54][C:53]2[C:48](=[CH:49][CH:50]=[C:51]([O:56]C)[CH:52]=2)[CH2:47]1)[CH3:38]>>[CH2:37]([N:39]([CH2:58][C:59]1[CH:64]=[CH:63][C:62]([O:65][CH2:66][CH2:67][N:68]2[CH2:73][CH2:72][CH2:71][CH2:70][CH2:69]2)=[C:61]([F:74])[CH:60]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[CH:46]1[CH2:55][CH2:54][C:53]2[CH:52]=[C:51]([OH:56])[CH:50]=[CH:49][C:48]=2[CH2:47]1)[CH3:38]
Reactant: CCN(Cc1ccc(OCCN2CCCCC2)c(F)c1)c1ccccc1C1CCc2cc(OC)ccc2C1
Agent: COc1ccc2c(c1)CCC(c1ccccc1NCc1ccc(OCCN3CCCCC3)c(F)c1)C2
Product: CCN(Cc1ccc(OCCN2CCCCC2)c(F)c1)c1ccccc1C1CCc2cc(O)ccc2C1
Yield: 86.7 %

Procedure:
Synthesized from [3-fluoro-4-(2-piperidin-1-ylethoxy)benzyl][2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine according to an analogous synthetic method to Example 36, ethyl [3-fluoro-4-(2-piperidin-1-ylethoxy)benzyl][2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine (332 mg) was used according to an analogous synthetic method to Example 111 to provide the title compound (280 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:17])[N:7]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12][C:8]3=[N:9][C:10]=2[CH:11]=1.C([O-])([O-])=O.[K+].[K+].I[CH2:25][CH3:26]>CC(C)=O.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:17])[N:7]3[CH2:16][CH2:15][N:14]([CH2:25][CH3:26])[CH2:13][CH2:12][C:8]3=[N:9][C:10]=2[CH:11]=1
Reactant: CCI
Reactant: O=c1c2ccc(Br)cc2nc2n1CCNCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCN1CCc2nc3cc(Br)ccc3c(=O)n2CC1

Procedure:
A solution of 8-bromo-2,3,4,5-tetrahydro-[1,4]diazepino[7,1-b]quinazolin-11(1H)-one (100 mg, 0.34 mmol), K2CO3 (188 mg, 1.36 mmol) and excess iodoethane in acetone (20 mL) was stirred at room temperature overnight. Then the reaction mixture was diluted with water (80 mL) and extracted with ethyl acetate (3×70 mL). The combined organic layers were dried over Na2SO4. After filtration and concentration, the residue was purified by silica gel chromatography to give 100 mg of the desired product. MS (ESI): 322, 324 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH2:18]([C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1)[CH2:19][CH2:20][CH3:21].CCCCCC.CCOC(C)=O>C1COCC1>[CH2:18]([C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([N:15]2[CH2:16][CH2:17][N:12]([C:6]3[C:5]4[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:9]=[CH:8][CH:7]=3)[CH2:13][CH2:14]2)=[O:30])=[CH:24][CH:23]=1)[CH2:19][CH2:20][CH3:21]
Reactant: Clc1ccc2c(N3CCNCC3)ccnc2c1
Reactant: CCCCc1ccc(N=C=O)cc1
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCc1ccc(NC(=O)N2CCN(c3ccnc4cc(Cl)ccc34)CC2)cc1

Procedure:
7-Chloro-4-(piperazin-1-yl)quinoline (62 mg, 0.25 mmol) and 4-(n-butyl)phenyl isocyanate (57 μL, 0.30 mmol) in THF (10 mL) are reacted according to method C yielding the title product as a colorless solid after column chromatography with hexane-EtOAc.
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1[CH:5]=[C:6]([C:10](=[O:12])[CH3:11])[CH:7]=[CH:8][CH:9]=1>C(OCC)C>[Br:1][CH2:11][C:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH3:3])[CH:5]=1)=[O:12]
Reactant: BrBr
Reactant: CC(=O)c1cccc(C)c1
Solvent: CCOCC
Product: Cc1cccc(C(=O)CBr)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.4 %

Procedure:
Bromine (2.38 g, 14.9 mmol) was slowly added dropwise to a solution of 1-[3-methylphenyl]ethanone (2.00 g, 14.9 mmol) in diethyl ether (50 ml), and the mixture was stirred at room temperature for 4 hours. The reaction mixture was distilled off under reduced pressure to give 3.03 g (95.3%) of the desired product as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:11][C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[N+:19]([O-])=O)[C:9]#N)=[CH:4][CH:3]=1>C1COCC1.CO.[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:11][C:12]3[C:13](=[CH:14][CH:15]=[C:16]([CH3:18])[CH:17]=3)[NH:19][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Cc1ccc([N+](=O)[O-])c(CC(C#N)c2ccc(F)cc2)c1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)CC(c1ccc(F)cc1)CN2
Temperature: 40 °C
Reaction time: 24 h
Yield: 31.6 %

Procedure:
A mixture of 2-(4-fluorophenyl)-3-(5-methyl-2-nitrophenyl)propanenitrile (0.3 g, 0.00105 mol), and 10% Pd on Carbon (0.180 g) in THF (1 mL) and MeOH (6 mL) was stirred under atmospheric hydrogen pressure at 40° C. for 24 h. After completion of reaction (monitored by TLC), the catalyst was removed by filtration through Celite. The filtrate was concentrated under reduced pressure, and the product was purified by column chromatography (4% EtOAc:hexane in silica 100-200 mesh, diameter of column—5.0 cm, height of silica—approx. 5 inch) to give the desired compound as a yellow colored solid (0.080 g, 33% yield).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:20]2OC3[C:13](=CC=CC=3)[NH:12][C:11]=2C=C[CH:8]=1.NCCC1CCCN1C.[Cl-].[Al+3].[Cl-].[Cl-].CO>ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]1[CH2:8][N:12]([CH3:13])[CH2:11][CH2:20]1
Reactant: c1ccc(-c2cccc3c2Oc2ccccc2N3)nc1
Agent: CN1CCCC1CCN
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CO
Product: CN1CCC(c2ccccn2)C1
Reaction time: 1 h
Yield: 57.4 %

Procedure:
4-Pyridinyl phenoxazine (13 mg, 0.1181 mmol), 2-(2-aminoethyl)-1-methylpyrrolidine (22 ul, 0.1518 mmol) and aluminum chloride (27 mg, 0.2025 mmol) were mixed in anhydrous dichloromethane (1 ml) and stirred for 1 h. The mixture was then evaporated to a residue which was washed with saturated aqueous sodium potassium tartaric acid. The mixture was then extracted with 3×10 ml dichloromethane and the extracts dried (Na2SO4) and evaporated. The compound was then isolated using preparative thin layer chromatography (Al2O3, 3% MeOH in dichloromethane) to yield the 4-pyridinyl methylpyrrolidine (11 mg) as a yellow solid.