Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:20]([CH3:21])=[CH:19][C:18]([Cl:22])=[CH:17][C:16]=4[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([NH2:27])[CH2:25][CH3:26])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:35](OC(=O)C)(=[O:37])[CH3:36]>O1CCCC1.C(=O)(O)[O-].[Na+]>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:20]([CH3:21])=[CH:19][C:18]([Cl:22])=[CH:17][C:16]=4[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([NH:27][C:35](=[O:37])[CH3:36])[CH2:25][CH3:26])=[CH:4][CH:3]=1
Reactant: CCC(N)c1ccc(Cl)c2nc3n(c12)CCCN3c1c(C)cc(Cl)cc1Cl
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC(NC(C)=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1c(C)cc(Cl)cc1Cl

Procedure:
Ethylmagnesium bromide (3 M solution in diethyl ether, 4.50 mL, 13.5 mmol) was added to a stirred suspension of 9-chloro-1-(2,4-dichloro-6-methylphenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carbonitrile (530 mg, 1.35 mmol) in tetrahydrofuran (14 mL) at room temperature. After the resultant mixture was refluxed for 3 hr, a suspension of sodium tetrahydroborate (1.02 g, 27.0 mmol) in 2-propanol (14 mL) was added at room temperature. The resultant mixture was stirred at 50° C. for 30 min, diluted with water, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give crude 1-[9-chloro-1-(2,4-dichloro-6-methylphenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propan-1-amine (609 mg), which was used for the next step without further purification. To a mixture of crude 1-[9-chloro-1-(2,4-dichloro-6-methylphenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propan-1-amine (120 mg) and triethylamine (0.0742 mL, 0.532 mmol) in tetrahydrofuran (2.7 mL) was added acetic anhydride (0.0302 mL, 0.319 mol) at 0° C. The resultant mixture was stirred at room temperature for 10 min, diluted with aqueous sodium bicarbonate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 20-100% ethyl acetate/n-hexane gradient mixture and preparative HPLC eluting with a 10-40% acetonitrile/water gradient mixture to give the two title compounds as colorless solids.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=1)[CH2:12][CH2:13][C:14](O)=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:27]C1C(Cl)=CC=CC=1CCN.C(Cl)(=O)C(Cl)=O.CN(C=O)C>ClCCl>[Cl:27][C:14](=[O:15])[CH2:13][CH2:12][N:11]([CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=1)[C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CCN(CCc1ccc(Cl)c(Cl)c1)C(=O)OCc1ccccc1
Reactant: NCCc1cccc(Cl)c1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)CCN(CCc1ccc(Cl)c(Cl)c1)C(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
3-((Benzyloxycarbonyl)(3,4-dichlorophenethyl)amino)propanoic acid (0.5 g), prepared according to the procedure of Example 1 step iv), but using 2,3-dichlorophenethylamine instead of phenethylamine, was dissolved in dichloromethane (10 mL) and treated with oxalyl chloride (0.132 mL) and DMF (0.05 mL). The reaction was stirred at room temperature until gas evolution ceased, and the solvent was removed in vacuo to give an oil which was used in step ii) directly.
Reaction SMILES: [C:1]1([CH:7]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([C:20]4[CH:21]=[C:22](B5OC(C)(C)C(C)(C)O5)[CH:23]=[CH:24][C:19]=4[O:18][CH2:17]3)[C:9]2=[O:34])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:41]O.[OH-].[Na+]>CO>[C:35]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([C:20]4[CH:21]=[C:22]([OH:41])[CH:23]=[CH:24][C:19]=4[O:18][CH2:17]3)[C:9]2=[O:34])[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: CC1(C)OB(c2ccc3c(c2)C2(CO3)C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)OC1(C)C
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C12COc1ccc(O)cc12
Temperature: 0 °C
Reaction time: 16 h
Yield: 89.7 %

Procedure:
A mixture of 1′-(diphenylmethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)one (4.50 g, 8.50 mmol), hydrogen peroxide (4.86 mL, 30% solution, 42.5 mmol), sodium hydroxide (16.38 mL, 10% solution, 40.82 mmol) in methanol was stirred at 0° C. for 30 min and ambient temperature for 16 h. The reaction mixture was quenched with sodium bisulfite. The pH of the reaction mixture was adjusted to 4 using 14% hydrochloric acid. The mixture was extracted with ethyl acetate (3×250 mL). The combined organic layers was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was triturated with hexane (20.0 mL), followed by ether (15.0 mL) to give the title compound (3.20 g, 90%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 7.45-7.38 (m, 10H), 7.13 (dd, 1H), 7.07-6.91 (m, 3H), 6.79 (d, 1H), 6.63 (dd, 1H), 6.50 (d, 1H), 6.12 (d, 1H), 4.96 (d, 1H), 4.69 (d, 1H); MS (ES+) m/z 420.23 (M+1).
Reaction SMILES: Cl.Cl[C:3]1[N:8]=[CH:7][N:6]=[C:5]([N:9]2[C:13](=[O:14])[C:12]([N:15]3[CH:19]=[CH:18][N:17]=[CH:16]3)=[CH:11][NH:10]2)[CH:4]=1.Cl.[F:21][C:22]1([F:26])[CH2:25][NH:24][CH2:23]1.C(N(C(C)C)C(C)C)C>O1CCCC1>[F:21][C:22]1([F:26])[CH2:25][N:24]([C:3]2[N:8]=[CH:7][N:6]=[C:5]([N:9]3[C:13](=[O:14])[C:12]([N:15]4[CH:19]=[CH:18][N:17]=[CH:16]4)=[CH:11][NH:10]3)[CH:4]=2)[CH2:23]1
Reactant: O=c1c(-n2ccnc2)c[nH]n1-c1cc(Cl)ncn1
Reactant: FC1(F)CNC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=c1c(-n2ccnc2)c[nH]n1-c1cc(N2CC(F)(F)C2)ncn1

Procedure:
100 mg (0.3 mmol) of the compound from Example 13A, 52 mg (0.4 mmol) of 3,3-difluoroazetidine hydrochloride and 175 ml (130 mg, 1.0 mmol) of N-ethyl-N-(propan-2-yl)propane-2-amine are initially charged in 2 ml of tetrahydrofuran and reacted in a single mode microwave (Emrys Optimizer) at 120° C. for 3 h. The precipitated solid is filtered off and the filtrate is concentrated under reduced pressure. The residue is taken up in acetonitrile/water and purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient). Yield: 36 mg (32% of theory)
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:7]=1[CH3:13])=[O:4].[C:14](O)(=O)C>>[Cl:12][C:8]1[C:7]([CH3:13])=[C:6]([N:5]2[C:3](=[O:4])[CH2:2][NH:1][CH2:14]2)[CH:11]=[CH:10][CH:9]=1
Reactant: CC(=O)O
Reactant: Cc1c(Cl)cccc1NC(=O)CN
Product: Cc1c(Cl)cccc1N1CNCC1=O
Temperature: 90 °C

Procedure:
A mixture of 2-amino-N-(3-chloro-2-methyl-phenyl)-acetamide (74) (1.18 g, 1 equiv), paraformaldehyde (HCHO)n (0.77 g, 1.5 equiv) and 3 mL of acetic acid was heated at 90° C. for 3 h and evaporated to dryness to afford 3-(3-chloro-2-methyl-phenyl)-imidazolidin-4-one (75) as acetic acid salt.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[C@:11]1([CH3:20])[CH2:16][S:15](=[O:18])(=[O:17])[CH2:14][C:13]([NH2:19])=[N:12]1.C(N(CC)CC)C>C(O)C.[Pd]>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C@:11]2([CH3:20])[CH2:16][S:15](=[O:17])(=[O:18])[CH2:14][C:13]([NH2:19])=[N:12]2)[CH:4]=1
Reactant: C[C@@]1(c2cc([N+](=O)[O-])ccc2F)CS(=O)(=O)CC(N)=N1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: C[C@@]1(c2cc(N)ccc2F)CS(=O)(=O)CC(N)=N1
Yield: 87.6 %

Procedure:
A solution of (R)-5-(2-fluoro-5-nitro-phenyl)-5-methyl-1,1-dioxo-1,2,5,6-tetrahydro-1λ6-[1,4]thiazin-3-ylamine (584 mg, 1.94 mmol, Eq: 1.00) in ethanol (45 ml), triethylamine (196 mg, 270 μl, 1.94 mmol, Eq: 1.00) and Pd/C (206 mg, 194 μmol, Eq: 0.1) was hydrogenated at room temperature for 1 hour. Filtered off the catalyst, washed with ethanol, evaporated the filtrate and dried in HV to give the (R)-5-(5-amino-2-fluoro-phenyl)-5-methyl-1,1-dioxo-1,2,5,6-tetrahydro-1λ6-[1,4]thiazin-3-ylamine (460 mg, 1.7 mmol, 87.5% yield) as a an off-white foam. MS (ISP): m/z=272.4 [M+H]+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[N+:7](C1C=C([N+]([O-])=O)C=CC=1ON)([O-])=O.[C:21]([C:23]1[CH:28]=[CH:27][C:26]([N:29]2[C:34](=[O:35])[CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[NH:31][C:30]2=[O:40])=[CH:25][C:24]=1[O:41][CH3:42])#[N:22]>C(OCC)(=O)C>[NH2:7][N:31]1[C:32]([C:36]([F:39])([F:38])[F:37])=[CH:33][C:34](=[O:35])[N:29]([C:26]2[CH:27]=[CH:28][C:23]([C:21]#[N:22])=[C:24]([O:41][CH3:42])[CH:25]=2)[C:30]1=[O:40]
Reactant: COc1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)ccc1C#N
Reactant: NOc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: COc1cc(-n2c(=O)cc(C(F)(F)F)n(N)c2=O)ccc1C#N
Temperature: 57.5 °C
Reaction time: 15 h
Yield: 52 %

Procedure:
Potassium carbonate (1.0 g) and 2,4-dinitrophenoxyamine (0.8 g) were added to a solution of 3-[4-cyano-3-methoxyphenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (1.1 g) in 15 ml of ethyl acetate. The mixture was subsequently stirred for 15 hours at 55-60° C., whereupon the solids formed were separated off and washed using in each case 30 ml of ethyl acetate and diisopropyl ether. The combined filtrates were washed twice using in each case 25 ml of water, dried over sodium sulfate and then concentrated. After crystallization using 10 ml of diisopropyl ether, 0.6 g of the desired product was obtained. M.p.: >230° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[NH2:18][C:19]1[C:24]([CH3:25])=[CH:23][N:22]=[C:21]([OH:26])[N:20]=1>>[OH:26][C:21]1[N:20]=[C:19]([NH:18][C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[N:3]=2)[C:24]([CH3:25])=[CH:23][N:22]=1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Reactant: Cc1cnc(O)nc1N
Product: Cc1cnc(O)nc1Nc1cc(C(F)(F)F)nc(-c2cccnc2)n1

Procedure:
The title compound was prepared from 4-chloro-2-(3-pyridinyl)-6-trifluoromethylpyrimidine (50 mg, 0.192 mmol) and 4-amino-2-hydroxy-5-methylpyrimidine (36 mg, 0.288 mmol) similar to Example 190 and was isolated as a solid. 1H NMR (CDCl3): 9.47 (brs, 1H), 8.59–8.54 (m, 2H), 7.28 (dd, J=8.1, 5.1 Hz, 1H), 6.59 (s, 1H), 5.18 (s, 2H), 1.70 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[N:16][C:5]2[NH:6][C:7]3[CH2:15][CH:14]4[N:10]([CH2:11][CH2:12][CH2:13]4)[CH2:9][C:8]=3[C:4]=2[CH:3]=1.[OH-].[K+].[F:20][C:21]([F:31])([F:30])[C:22]1[CH:27]=[CH:26][C:25]([CH:28]=[CH2:29])=[CH:24][N:23]=1>CN1C(=O)CCC1.O>[CH3:1][C:2]1[CH:17]=[N:16][C:5]2[N:6]([CH2:29][CH2:28][C:25]3[CH:24]=[N:23][C:22]([C:21]([F:31])([F:20])[F:30])=[CH:27][CH:26]=3)[C:7]3[CH2:15][CH:14]4[N:10]([CH2:11][CH2:12][CH2:13]4)[CH2:9][C:8]=3[C:4]=2[CH:3]=1
Reactant: C=Cc1ccc(C(F)(F)F)nc1
Reactant: Cc1cnc2[nH]c3c(c2c1)CN1CCCC1C3
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1cnc2c(c1)c1c(n2CCc2ccc(C(F)(F)F)nc2)CC2CCCN2C1
Reaction time: 16 h

Procedure:
A solution of 3-methyl-7,8,9,9a,10,11-hexahydro-5H-pyrido[3′,2′:4,5]pyrrolo[3,2-f]indolizine (100 mg, 0.44 mmol) and powdered KOH (172.6 mg, 3.038 mmol) in NMP (2 mL) was stirred at RT for 5 min. 2-(Trifluoromethyl)-5-vinylpyridine (152 mg, 0.881 mmol) was added into the reaction mixture and stirring continued for 16 h at RT. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue obtained was purified by silica gel flash chromatography to yield 3-methyl-11-(2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-7,8,9,9a,10,11-hexahydro-5H-pyrido[3′,2′:4,5]pyrrolo[3,2-f]indolizine;
Reaction SMILES: [O:1]=[S:2]1(=[O:30])[C:7]2[CH:8]=[C:9]([O:12][C:13]3[CH:14]=[C:15]([P:19](=[O:26])([O:23]CC)[O:20]CC)[CH:16]=[CH:17][CH:18]=3)[CH:10]=[CH:11][C:6]=2[N:5]2[CH2:27][CH2:28][CH2:29][CH:4]2[NH:3]1.Br[Si](C)(C)C>C(#N)C>[O:30]=[S:2]1(=[O:1])[C:7]2[CH:8]=[C:9]([O:12][C:13]3[CH:14]=[C:15]([P:19](=[O:20])([OH:26])[OH:23])[CH:16]=[CH:17][CH:18]=3)[CH:10]=[CH:11][C:6]=2[N:5]2[CH2:27][CH2:28][CH2:29][CH:4]2[NH:3]1
Reactant: CCOP(=O)(OCC)c1cccc(Oc2ccc3c(c2)S(=O)(=O)NC2CCCN32)c1
Agent: C[Si](C)(C)Br
Solvent: CC#N
Product: O=P(O)(O)c1cccc(Oc2ccc3c(c2)S(=O)(=O)NC2CCCN32)c1
Reaction time: 0.5 h

Procedure:
Acetonitrile (20 ml), 0.66 mmol of the product of Example 52 and 1.98 mmol of bromotrimethylsilane are stirred at reflux for 1 h. The solvent and the excess of reagent are evaporated off in vacuo and the residue is taken up in solution in 10 ml of methanol. After stirring for 30 min., the solution is evaporated to dryness and the residue is taken up in 1N HCl. A gum is obtained which is crystallised by adding a small amount of CH2Cl2. The expected product is recovered by filtration.
Reaction SMILES: [C:1]1([C:7]2[N:22]=[C:10]3[CH:11]=[C:12]([C:16]4[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=4)[CH:13]=[C:14]([NH2:15])[N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:23]1([CH2:29][CH2:30][C:31](Cl)=[O:32])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:23]1([CH2:29][CH2:30][C:31]([NH:15][C:14]2[N:9]3[N:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:22]=[C:10]3[CH:11]=[C:12]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[CH:13]=2)=[O:32])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: Nc1cc(-c2ccncc2)cc2nc(-c3ccccc3)nn12
Product: O=C(CCc1ccccc1)Nc1cc(-c2ccncc2)cc2nc(-c3ccccc3)nn12

Procedure:
The title compound, MS m/e (%): 420 (M+H+, 100), was prepared in accordance with the general method of example 31 from 2-phenyl-7-pyridin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-5-ylamine and phenylpropionyl chloride.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.[OH-].[Na+].O.[C:12]1([CH3:24])[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[C:13]=1[S:20](Cl)(=[O:22])=[O:21]>C1(C)C=CC=CC=1>[C:12]1([CH3:24])[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[C:13]=1[S:20]([O:7][C:6]1[CH:5]=[CH:4][C:3]([CH3:8])=[CH:2][CH:1]=1)(=[O:21])=[O:22]
Reactant: Cc1ccc(O)cc1
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(OS(=O)(=O)c2c(C)cc(C)cc2C)cc1
Reaction time: 1 h

Procedure:
10.8 g of p-cresol is added to a mixture containing 9.17 g of 48% NaOH, 50 ml of water and 50 ml of toluene. To the resulting mixture is added 22.9 g of mesitylenesulfonyl chloride, and reaction is carried out at 60° to 65° C. for 1 hour. After separating the aqueous layer, toluene is removed from the toluene layer by distillation. The resulting desired compound is purified with methanol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][O:6][CH2:7][C:8]1[N:13]=[C:12]([NH2:14])[CH:11]=[CH:10][CH:9]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][C:20]=1[C:29]([F:32])([F:31])[F:30]>>[F:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:14][C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([CH2:7][O:6][CH2:5][C:4]3[CH:15]=[CH:16][CH:17]=[C:2]([F:1])[CH:3]=3)[N:13]=2)(=[O:26])=[O:27])=[CH:21][C:20]=1[C:29]([F:32])([F:30])[F:31]
Reactant: O=S(=O)(Cl)c1ccc(F)c(C(F)(F)F)c1
Reactant: Nc1cccc(COCc2cccc(F)c2)n1
Product: O=S(=O)(Nc1cccc(COCc2cccc(F)c2)n1)c1ccc(F)c(C(F)(F)F)c1

Procedure:
This material was prepared in analogy to example 1 from 6-(3-fluoro-benzyloxymethyl)-pyridin-2-ylamine (0.06 g) and 4-fluoro-3-(trifluoromethyl)-benzenesulfonyl chloride (0.075 g) as a light yellow solid (0.1 g). MS (ESI−): 457.2 ([M−H]−).
Reaction SMILES: S(=O)(=O)(O)O.N[C:7]1[CH:16]=[C:15]2[C:10]([C:11]([Br:21])=[N:12][N:13]([CH:18]([CH3:20])[CH3:19])[C:14]2=[O:17])=[CH:9][CH:8]=1.N([O-])=[O:23].[Na+].NC(N)=O>CC(O)=O.O>[OH:23][C:7]1[CH:16]=[C:15]2[C:10]([C:11]([Br:21])=[N:12][N:13]([CH:18]([CH3:20])[CH3:19])[C:14]2=[O:17])=[CH:9][CH:8]=1
Reactant: CC(C)n1nc(Br)c2ccc(N)cc2c1=O
Reactant: O=N[O-]
Agent: NC(N)=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)n1nc(Br)c2ccc(O)cc2c1=O
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 93.2 %

Procedure:
Concentrated sulfuric acid (17 ml) was added slowly to a solution of 7-Amino-2-Isopropyl-4-bromo-2H-phthalazin-1-one (4.6 g, 0.016 mol) in HOAc (50 ml). The reaction mixture was cooled to 0° C. and a solution of NaNO2 (1.52 g, 0.022 mol) in water (10 ml) was added dropwise. The reaction mixture was stirred for a further 20 min at 0° C. prior to the addition of urea (0.55 g, 0.009 mol) and cold water (50 ml). The reaction mixture was then added carefully to a refluxing mixture of sulfuric acid (28 ml) in water (115 ml) and the reaction was stirred for a further 10 min at reflux before being allowed to cool to RT. Upon standing, an orange precipitate was observed, which was collected by filtration and washed with water to give the title compound (4.22 g, 93% yield) as an orange powder.
Reaction SMILES: [CH3:1][C:2]([CH3:39])([CH3:38])[CH2:3][CH2:4][C@:5]1([CH3:37])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([OH:15])=[C:7]([C:16]2[NH:21][C:20]3[CH:22]=[CH:23][C:24]([NH:26]C(=O)OC(C)(C)C)=[CH:25][C:19]=3[S:18](=[O:35])(=[O:34])[N:17]=2)[C:6]1=[O:36].Cl.O1CCOCC1>ClCCl>[NH2:26][C:24]1[CH:23]=[CH:22][C:20]2[NH:21][C:16]([C:7]3[C:6](=[O:36])[C@@:5]([CH2:4][CH2:3][C:2]([CH3:1])([CH3:38])[CH3:39])([CH3:37])[C:14]4[C:9]([C:8]=3[OH:15])=[CH:10][CH:11]=[CH:12][CH:13]=4)=[N:17][S:18](=[O:35])(=[O:34])[C:19]=2[CH:25]=1
Reactant: CC(C)(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NC(=O)OC(C)(C)C)ccc3N2)=C(O)c2ccccc21
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21
Yield: 69.8 %

Procedure:
To a solution of the product of Example 49-5 (185.0 g, 0.334 mol) in dichloromethane (220 mL) was added 4 M HCl in dioxane (430 mL, 1.72 mol) and the solution was mixed at room temperature for 3.5 h. The reaction was quenched by addition of ethyl acetate (1 L) and pH 7 phosphate buffer (1.5 L) and the layers were separated. The organic layer was concentrated and chased with ethanol to a final volume of approximately 1100 mL. The product precipitated and was isolated by filtration and dried to give the title compound (105.79 g, 70%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:19][CH3:20])=[CH:5][C:6]2[S:12][CH2:11][CH2:10][CH:9]([C:13]([O:15]C)=[O:14])[C:8](=O)[C:7]=2[CH:18]=1.[BH4-].[Na+].Cl>CO.C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]([O:19][CH3:20])=[CH:5][C:6]2[S:12][CH2:11][CH2:10][C:9]([C:13]([OH:15])=[O:14])=[CH:8][C:7]=2[CH:18]=1
Reactant: COC(=O)C1CCSc2cc(OC)c(OC)cc2C1=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1cc2c(cc1OC)SCCC(C(=O)O)=C2
Reaction time: 6 h
Yield: 63.4 %

Procedure:
In a mixture solvent of methanol (50 ml) and methylene chloride (50 ml) is dissolved methyl 7,8-dimethoxy-5-oxo-2,3,4,5-tetrahydro-1-benzothiepin-4-carboxylate (11.4 g) obtained in Reference Example 8. To the solution is added sodium borohydride (2.1 g) in limited amounts taking 6 hours with stirring. Excess sodium borohydride is decomposed with dilute hydrochloric acid, followed by extraction with methylene chloride. The organic layer is washed with a small volume of saturated aqueous saline, dried, and concentrated under reduced pressure. The residue is dissolved in methanol (50 ml), to the solution is added a 7.5 N aqueous solution of sodium hydroxide (10 ml), and the mixture is stirred at room temperature for 1.5 hour. To the reaction mixture is added water. The mixture is acidified (pH 3) with dilute hydrochloric acid, followed by extraction with methylene chloride. The organic layer is concentrated under reduced pressure, and the concentrate is dissolved in dioxane (35 ml). To the solution is added 10N hydrochloric acid (7 ml), and the mixture is stirred at 50° C. for 30 minutes. The reaction mixture is cooled and diluted with water. Then precipitating crude crystals are collected by filtration, washed with water and dried, followed by recrystallization from methylene chloride-ether to give 7,8-dimethoxy-2,3-dihydro-1-benzothiepin-4-carboxylic acid as colorless prisms (6.5 g),
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([NH:5][C:6]1[CH:16]=[CH:15][C:9]([CH:10]=[CH:11][C:12]([OH:14])=O)=[CH:8][CH:7]=1)=[O:4].[NH2:19][CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1.P(C#N)(OCC)(OCC)=O.C(N(CC)CC)C>CN(C)C=O>[N:23]1[CH:24]=[CH:25][CH:26]=[C:21]([CH2:20][NH:19][C:12](=[O:14])[CH:11]=[CH:10][C:9]2[CH:8]=[CH:7][C:6]([NH:5][C:3](=[O:4])[C:2]([F:1])([F:18])[F:17])=[CH:16][CH:15]=2)[CH:22]=1
Reactant: NCc1cccnc1
Reactant: O=C(O)C=Cc1ccc(NC(=O)C(F)(F)F)cc1
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(C=Cc1ccc(NC(=O)C(F)(F)F)cc1)NCc1cccnc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.3 %

Procedure:
A solution of 4-(trifluoroacetylamino)cinnamic acid (1.30 g) and 3-(aminomethyl)pyridine (540 mg) in 20 ml dimethylformamide was mixed with 0.9 ml diethyl cyanophosphate and subsequently with 0.8 ml triethylamine on ice, and then stirred at room temperature for 4 hours. The solid precipitated from water was then filtered, washed with water, and dried by heating under reduced pressure to give N-(3-pyridylmethyl)-4-[(trifluoroacetyl)amino]cinnamamide (1.61 g, 92%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([CH3:3])=[CH2:2].[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl>C1(C)C=CC=CC=1>[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:1]([C:4]2[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=2)([CH3:3])[CH3:2])=[CH:14][CH:13]=1
Reactant: C=C(C)c1ccc(O)cc1
Reactant: Nc1ccccc1
Agent: Cl
Solvent: Cc1ccccc1
Product: CC(C)(c1ccc(N)cc1)c1ccc(O)cc1
Temperature: 150 °C
Reaction time: 3 h

Procedure:
A mixture of 134.0 grams (1.0 mole) of p-isopropenylphenol and 186.0 grams (2.0 moles) of aniline was stirred and heated to 150° C. To the mixture was added 5.0 grams of a solution obtained by adding 1.28 grams of 10% hydrochloric acid to 93 grams of aniline and stirring the mixture well. The reaction was carried out for 3.0 hours (10,800 s) at the 150° C. reaction temperature. The reaction product was cooled to 120° C. then 350 milliliters of toluene was added. The product was then cooled to 25° C. and the solid precipitated product was recovered by filtration. The crude product was slurried into 350 milliliters of methanol and heated to a reflux then maintained for 15 minutes (900 s). After cooling, the product was recovered by filtration and dried under vacuum to yield 4-(1-(4-aminophenyl)-1-methylethyl)phenol as a white powder.
Reaction SMILES: [CH2:1]([C:9]1[C:10]([C:22]([F:25])([F:24])[F:23])=[C:11]2[C:15]3=[C:16]([CH2:18][NH:19][CH2:20][CH2:21][N:14]3[CH:13]=[CH:12]2)[CH:17]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.[CH3:27][N:28]([CH3:33])[CH2:29][C:30](O)=[O:31].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C1COCC1>[CH3:27][N:28]([CH3:33])[CH2:29][C:30]([CH:20]1[NH:19][CH2:18][C:16]2=[C:15]3[C:11](=[C:10]([C:22]([F:25])([F:24])[F:23])[C:9]([CH2:1][CH2:2][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=4)=[CH:17]2)[CH:12]=[CH:13][N:14]3[CH2:21]1)=[O:31]
Reactant: CN(C)CC(=O)O
Reactant: FC(F)(F)c1c(CCc2ccccc2)cc2c3c1ccn3CCNC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C)CC(=O)C1Cn2ccc3c(C(F)(F)F)c(CCc4ccccc4)cc(c32)CN1
Reaction time: 8 h

Procedure:
To 6-phenethyl-7-(trifluoromethyl)-1,2,3,4-tetrahydro-[1,4]diazepino[6,7,1-hi]indole (prepared as described in Example 2 above, 37 mg, 0.1 mmol) and N,N-dimethylglycine hydrochloride (14 mg, 0.1 mmol) in THF (7 mL) was added triethylamine (50 mg, 0.5 mmol), and 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU; 43 mg, 0.1 mmol). The resulting mixture was stirred overnight, then partitioned between ethyl acetate and water. The organic phase was washed sequentially with NaHCO3 and brine, then dried and concentrated. The residue was purified by reverse-phase chromatography (acetonitrile/water/trifluoroacetic add) to yield 2-(dimethylamino)-1-(6-phenethyl-7-(trifluoromethyl)-3,4-dihydro-[1,4]diazepino[6,7,1-hi]indol-2(1H)-yl)ethanone.