Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[CH:21]=[C:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:19]=[C:18]([NH2:28])[N:17]=3)=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[N:29]1([CH2:35][CH2:36][OH:37])[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.[OH-].[K+].C1OCCOCCOCCOCCOCCOC1>C1(C)C=CC=CC=1.O>[N:29]1([CH2:35][CH2:36][O:37][C:2]2[CH:7]=[C:6]([O:8][C:9]3[CH:14]=[CH:13][C:12]([NH:15][C:16]4[CH:21]=[C:20]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[N:19]=[C:18]([NH2:28])[N:17]=4)=[CH:11][CH:10]=3)[CH:5]=[CH:4][N:3]=2)[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1
Reactant: OCCN1CCOCC1
Reactant: Nc1nc(Nc2ccc(Oc3ccnc(Cl)c3)cc2)cc(-c2ccccc2)n1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: Nc1nc(Nc2ccc(Oc3ccnc(OCCN4CCOCC4)c3)cc2)cc(-c2ccccc2)n1
Temperature: 90 °C
Reaction time: 8 h
Yield: 15.2 %

Procedure:
N4-[4-(2-chloro-pyridin-4-yloxy)-phenyl]-6-phenyl-pyrimidine-2,4-diamine (Example 48, 75 mg, 0.19 mmol) was dissolved in toluene (1.5 mL). 2-Morpholin-4-yl-ethanol (61 mg, 0.46 mmol), powdered KOH (22 mg, 0.38 mmol), and 18-crown-6 (20 mg, 0.08 mmol) were subsequently added. The mixture was stirred at 90° C. overnight, after which time it was diluted with water and extracted with both ethyl acetate and dichloromethane. The combined organic extracts were concentrated and the residue was purified by prep HPLC to give the title compound (14 mg, 15%). 1H NMR (DMSO-d6) δ 10.79 (br s, 1H), 9.99 (br s, 1H), 8.08 (d, J=5.8 Hz, 1H), 7.90 (m, 2H), 7.77 (dd, J=7.6, 2.0 Hz, 2H), 7.64 (m, 3H), 7.21 (d, J=8.9 Hz, 2H), 6.69 (dd, J=5.8, 2.1 Hz, 1H), 6.60 (s, 1H), 6.22 (d, J=2.2 Hz, 1H), 4.57 (t, J=5.1 Hz, 2H), 3.96 (m, 2H), 3.68 (m, 2H), 3.50 (m, 4H), 3.15 (m, 2H); MS ES: 485 (M+H)+, calcd 485, RT=1.96 min.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[CH:5]=[N+]=[N-])[CH3:2].[CH:9]1([CH2:12][OH:13])[CH2:11][CH2:10]1.CC(=O)OCC>C(Cl)Cl>[CH:9]1([CH2:12][O:13][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:8])[CH2:11][CH2:10]1
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: OCC1CC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)COCC1CC1
Temperature: 0 °C
Reaction time: 4 h
Yield: 90.3 %

Procedure:
Diazoacetic acid ethyl ester (80.00 g, 0.70 mol) was added dropwise to cyclopropanemethanol (60.66 g, 0.84 mol) and [Rh(Ac2O)2]2 (3.1 g, 7.02 mmol) in anhydrous CH2Cl2 (800 mL) at 0° C. The mixture was stirred at 0° C. for 30 min and at room temperature for 4 h. CH2Cl2 extractive work up and silica gel chromatography (PE: EA=100:1-50:1) gave the title compound (100 g, 90.4% yield) as a colorless oil. 1H NMR: (CDCl3, 400 MHz) δ 4.23-4.19 (m, 2H), 4.09 (s, 2H), 3.38-3.36 (m, 2H), 1.27 (t, J=7.2 Hz, 3H), 1.10-1.07 (m, 1H), 0.57-0.52 (m, 2H), 0.24-0.20 (m, 2H).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:10]([NH:11][NH2:12])=[CH:9][C:8](=[O:13])[N:7]([CH3:14])[C:6]2=[O:15])[CH2:3][CH2:2]1.[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[CH:22][CH:21]=[C:20]2[CH:27]=O.[CH:29]([C:31]1[N:35]([CH3:36])[CH:34]=[C:33]([C:37]#[N:38])[CH:32]=1)=O>>[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[CH:22][CH:21]=[C:20]2[CH2:27][N:12]1[C:29]([C:31]2[N:35]([CH3:36])[CH:34]=[C:33]([C:37]#[N:38])[CH:32]=2)=[C:9]2[C:10]([N:5]([CH2:4][CH:1]3[CH2:2][CH2:3]3)[C:6](=[O:15])[N:7]([CH3:14])[C:8]2=[O:13])=[N:11]1
Reactant: Cn1c(=O)cc(NN)n(CC2CC2)c1=O
Reactant: O=Cc1ccnc2ccc(Cl)cc12
Reactant: Cn1cc(C#N)cc1C=O
Product: Cn1cc(C#N)cc1-c1c2c(=O)n(C)c(=O)n(CC3CC3)c2nn1Cc1ccnc2ccc(Cl)cc12

Procedure:
This compound was made following the procedure described above, startng with 1-(cyclopropylmethyl)-6-hydrazino-3-methylpyrimidine-2,4(1H,3H)-dione synthesized according to the procedure used in example 1 for the corresponding isobutyl substituted compound, and condensing first with 6-chloroquinoline-4-carbaldehyde, followed by 5-formyl-1-methyl-1H-pyrrole-3-carbonitrile. Mass: 500.11 (M+H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)[CH:2]=1.[F:16][C:17]1[CH:18]=[C:19]([C:23]2[N:24]=[C:25]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[S:26][CH:27]=2)[CH:20]=[CH:21][CH:22]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[F:16][C:17]1[CH:18]=[C:19]([C:23]2[N:24]=[C:25]([N:28]3[CH2:29][CH2:30][N:31]([C:8]([NH:7][C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)=[O:15])[CH2:32][CH2:33]3)[S:26][CH:27]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: Fc1cccc(-c2csc(N3CCNCC3)n2)c1
Reactant: O=C(Nc1cccnc1)OCC(Cl)(Cl)Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(Nc1cccnc1)N1CCN(c2nc(-c3cccc(F)c3)cs2)CC1
Temperature: 70 °C
Reaction time: 4 h
Yield: 50.4 %

Procedure:
A mixture of 2,2,2-trichloroethyl pyridin-3-ylcarbamate (225 mg, 0.835 mmol), 1-[4-(3-fluorophenyl)-1,3-thiazol-2-yl]piperazine (200 mg, 0.760 mmol) and diisopropylethylamine (0.265 ml, 1.52 mmol) in dimethylsulfoxide (2.5 ml) was stirred at 70° C. for 4 hours. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from a mixed solvent of hexane and ethyl acetate to give the desired product (147 mg, 50.5%) as a solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([O-:9])=[O:8].[CH3:10]O>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: CO
Reactant: O=C([O-])c1ccccn1
Product: COC(=O)c1ccccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29 %

Procedure:
1 g of the complex MoO5 (picolinate]- [H3O]+ was dissolved in 10 ml of methanol and stirred at room temperature for one hour. 0.4 g of a bright yellow solid precipitated from solution at this time and a yield of 29% was obtained. Analysis calculated for MoO9N2C13H12 : C, 35.78%; H, 2.78%; N, 6.42%; O [active], 14.75%; Mo, 22.00%. Found: C, 35.79%; H, 2.90%; N, 6.26%; O [active] 14.11%; Mo, 22.23%. Infrared analysis: [CO]=1745 cm-1 [strong], 1680 cm-1 [strong]; [O--O]=845 cm-1 [strong], 855 cm-1 [strong]; [Mo=O]=945 cm-1 [strong]. Nuclear magnetic resonance [C5ND5 ]: 4.40, singlet, 3H, [C(O)OCH3 ]; 8.2-10.4, multiplet, 8H, [C6H4NCO2 ].
Reaction SMILES: C(NC(C)C)(C)C.[CH2:8]([Li])[CH2:9][CH2:10][CH3:11].[CH3:13][O:14][C:15](=[O:26])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([S:23][CH3:24])=[C:19]([Cl:25])[CH:18]=1.[O:27]1CCC[CH2:28]1>CN1CCCN(C)C1=O.[Au]>[CH3:13][O:14][C:15](=[O:26])[CH:16]([C:17]1[CH:22]=[CH:21][C:20]([S:23][CH3:24])=[C:19]([Cl:25])[CH:18]=1)[CH2:11][C@H:10]1[CH2:9][CH2:8][CH2:28][O:27]1
Reactant: [Li]CCCC
Reactant: C1CCOC1
Reactant: COC(=O)Cc1ccc(SC)c(Cl)c1
Agent: [Au]
Solvent: CC(C)NC(C)C
Solvent: CN1CCCN(C)C1=O
Product: COC(=O)C(C[C@H]1CCCO1)c1ccc(SC)c(Cl)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 52 %

Procedure:
A solution of diisopropylamine (0.55 mL, 3.94 mmol) in dry tetrahydrofuran (10 mL) was cooled to −78° C. under argon and was then treated with a 2.5M solution of n-butyllithium in hexanes (1.51 mL, 3.78 mmol). The reaction mixture was stirred at −78° C. for 30 min and then treated dropwise with a solution of (3-chloro-4-methylsulfanyl-phenyl)-acetic acid methyl ester (0.72 g, 3.15 mmol) in dry tetrahydrofuran (3.5 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (1.2 mL). The reaction mixture turned gold in color and was allowed to stir at −78° C. for 1 h. The reaction mixture was then treated with a solution of trifluoromethanesulfonic acid (R)-tetrahydro-furan-2-yl methyl ester (0.959 g, 4.10 mmol) in dry tetrahydrofuran (2 mL). The reaction mixture was allowed to warm to 25° C., where it was stirred for 52 h. The reaction mixture was quenched with a saturated aqueous ammonium chloride solution (25 mL) and then concentrated in vacuo to remove tetrahydrofuran. The aqueous residue was extracted with ethyl acetate (3×50 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 9/1 hexanes/ethyl acetate eluted to 85/15 hexanes/ethyl acetate) afforded 2-(3-chloro-4-methylsulfanyl-phenyl)-3-(tetrahydro-furan-2(R)-yl)-propionic acid methyl ester (0.519 g, 52%) as a pale yellow oil: [α]23589=−19.02° (c=0.51, chloroform); EI-HRMS m/e calcd for C15H19ClO3S (M+) 314.0743, found 314.0743.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]([C:20]([F:23])([F:22])[F:21])[O:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([Cl:16])=[CH:11][C:10]=2[C:17]#[C:18][CH3:19])=[O:5])C.C1COCC1.CCO.O.Cl>O>[Cl:16][C:12]1[CH:13]=[C:14]2[C:9](=[C:10]([C:17]#[C:18][CH3:19])[CH:11]=1)[O:8][CH:7]([C:20]([F:23])([F:21])[F:22])[C:6]([C:4]([OH:5])=[O:3])=[CH:15]2
Reactant: CC#Cc1cc(Cl)cc2c1OC(C(F)(F)F)C(C(=O)OCC)=C2
Agent: Cl
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CC#Cc1cc(Cl)cc2c1OC(C(F)(F)F)C(C(=O)O)=C2
Temperature: 60 °C
Reaction time: 2 h
Yield: 15.6 %

Procedure:
To 0.320 g (1.01 mmole) of ethyl-6-chloro-8-prop-1-ynyl-2-(trifluoromethyl)-2H-chromene-3-carboxylate was added 5 mL of a solvent mixture of THF/EtOH/H2O (7:2:1) followed by 64 mg (1.52 mmole) of LiOH-H20. The mixture was stirred at 60° C. for two hours. The mixture was concd, treated with water and acidified with 0.5N HCl. The product precipitated out of solution and was washed three times with water. The resulting solid was dried to afford 0.050 g (16%) of a brown solid: 1H NMR (CDCl3/400 MHz) 1.83 (s,3H), 5.77 (q, 1H, J=6.8 Hz), 6.89 (d, 1H, J=2.4 Hz), 7.03 (d, 1H, J=2.4 Hz), 7.35 (s, 1H); MS (ES−) 315 (M−1, 100). HRMS (ES−) m/z calcd for (C14H8O3ClF3) 315.0030, found 315.0048.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][C@H:10]1[CH3:15].[Br:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[C:19]([S:26]([CH3:29])(=[O:28])=[O:27])[CH:18]=1>>[Br:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([N:12]2[CH2:13][CH2:14][N:9]([C:3]3[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=3[CH3:1])[C@H:10]([CH3:15])[CH2:11]2)=[O:22])=[C:19]([S:26]([CH3:29])(=[O:28])=[O:27])[CH:18]=1
Reactant: Cc1ccc(N2CCNC[C@H]2C)c(C)c1
Reactant: CS(=O)(=O)c1cc(Br)ccc1C(=O)O
Product: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)C[C@H]2C)c(C)c1
Yield: 73.2 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 67 and using (R)-1-(2,4-dimethylphenyl)-2-methylpiperazine (1.2 g) and 4-bromo-2-methanesulfonylbenzoic acid (1.7 g), (4-bromo-2-methanesulfonylphenyl)[(R)-4-(2,4-dimethylphenyl)-3-methylpiperazin-1-yl]methanone (2.0 g) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[S:26][N:25]=[CH:24][N:23]=2)=[N:10]1.Cl.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH:29]1[CH2:34][C:35]([OH:37])=[O:36]>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:10]=[C:11]([C:22]2[S:26][N:25]=[CH:24][N:23]=2)[NH:12][C:13]([CH2:20][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH:29]2[CH2:34][C:35]([OH:37])=[O:36])=[C:14]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)C1=C(CBr)NC(c2ncns2)=NC1c1ccc(F)cc1Br
Reactant: O=C(O)CC1COCCN1
Agent: Cl
Product: CCOC(=O)C1=C(CN2CCOCC2CC(=O)O)NC(c2ncns2)=NC1c1ccc(F)cc1Br
Yield: 33.3 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(1,2,4-thiadiazol-5-yl)-1,4-dihydropyrimidine-5-carboxylate (0.77 g, 1.53 mmol) was reacted with 2-(morpholin-3-yl)acetic acid hydrochloride (0.28 g, 1.53 mmol) according to the procedure as described in Example 1, Step C to give the title compound as a yellow solid (0.29 g, 33%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([C:13]#[N:14])=[C:5]2[N:15]1[CH2:20][CH2:19][N:18]([C:21]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)=[O:22])[CH2:17][CH2:16]1.Cl[CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)[C:7](=[O:12])[C:6]([C:13]#[N:14])=[C:5]2[N:15]1[CH2:16][CH2:17][N:18]([C:21]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)=[O:22])[CH2:19][CH2:20]1
Reactant: ClCCN1CCOCC1
Reactant: Cc1ccc2[nH]c(=O)c(C#N)c(N3CCN(C(=O)c4cccs4)CC3)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c(N1CCN(C(=O)c3cccs3)CC1)c(C#N)c(=O)n2CCN1CCOCC1
Temperature: 0 °C
Yield: 17.2 %

Procedure:
A solution of Compound 107 (1 g, 2.64 mmol), 4-(2-chloro ethyl) morpholine (2.45 g, 13.2 mmol), and potassium carbonate (3.64 g, 26.4 mmol) in DMF was heated overnight at 90° C. The solution was cooled and poured into ice water. The solids formed were filtered, washed by water, and dried. The crude product was purified by flash chromatography eluting with 0-110% methanol in ethylacetate gradient to yield 223 mg (17%) of white solids. M.P. 207° C. 1H NMR (DMSO-d6): δ 2.40 (s, 3H), 3.54 (m, 4H), 3.63 (m, 4H), 3.92 (m, 4H), 4.35 (m, 2H), 7.16 (dd, J=3.4, 4.8 Hz, 1H), 7.49 (m, 2H), 7.61 (m, 1H), 7.69 (s, 1H), 7.80 (d, J=5.2 Hz, 1H). EIMS m/z 492 (M+1). Anal. (C26H29N5O3S) C, H, N.
Reaction SMILES: I[C:2]1[C:6]2[C:7]([O:11]C)=[N:8][CH:9]=[CH:10][C:5]=2[N:4]([CH:13]([CH2:17][CH3:18])[CH2:14][O:15][CH3:16])[CH:3]=1.[C:19]([CH2:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)#[N:20].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:16][O:15][CH2:14][CH:13]([N:4]1[C:5]2[CH:10]=[CH:9][NH:8][C:7](=[O:11])[C:6]=2[C:2]([C:25]2[CH:26]=[CH:27][C:22]([CH2:21][C:19]#[N:20])=[CH:23][CH:24]=2)=[CH:3]1)[CH2:17][CH3:18]
Reactant: N#CCc1ccc(B(O)O)cc1
Reactant: CCC(COC)n1cc(I)c2c(OC)nccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(COC)n1cc(-c2ccc(CC#N)cc2)c2c(=O)[nH]ccc21
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 43.4 %

Procedure:
To a solution of 3-iodo-4-methoxy-1-(1-methoxybutan-2-yl)-1H-pyrrolo[3,2-c]pyridine (50.0 mg) obtained in Step A-2 of Example 17 in DMF (2 mL)/water (0.20 mL) were added (4-(cyanomethyl)phenyl)boronic acid (33.8 mg), tetrakis(triphenylphosphine)palladium(0) (15.9 mg) and potassium carbonate (38.3 mg). The reaction mixture was stirred under microwave irradiation at 130° C. for 30 min. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (20.2 mg).
Reaction SMILES: [CH2:1]([N:8]1[CH2:20][CH2:19][C:11]2[NH:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:23](I)[CH3:24]>CN(C=O)C>[CH2:1]([N:8]1[CH2:20][CH2:19][C:11]2[N:12]([CH2:23][CH3:24])[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(CN2CCc3[nH]c4ccccc4c3C2)cc1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1c2c(c3ccccc31)CN(Cc1ccccc1)CC2
Yield: 85 %

Procedure:
To a suspension of 2-benzyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole and NaH (1.1 equiv.) in DMF (10 mL) was added at 0° C., ethyl iodide (1 mmol) and stirred at RT overnight. The reaction mixture was quenched with a sat. solution of NH4Cl and extracted with EtOAc. The combined organic extracts were dried over anydrous Na2SO4 and purified by flash chromatography to afford 2-benzyl-5-ethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (85%).
Reaction SMILES: [Cl-].[Na+].[CH3:3][CH:4]([OH:117])[CH:5]1[NH:53][C:51](=[O:52])[CH:50]([CH2:54][CH2:55][CH2:56][CH2:57][NH2:58])[NH:49][C:47](=[O:48])[CH:46]([CH2:59][C:60]2[C:68]3[C:63](=[CH:64][CH:65]=[CH:66][CH:67]=3)[NH:62][CH:61]=2)[NH:45][C:43](=[O:44])[CH:42]([CH2:69][C:70]2[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=2)[NH:41][C:39](=[O:40])[CH:38]([CH2:76][C:77]2[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=2)[NH:37][C:35](=[O:36])[CH:34]([CH2:83][C:84]([NH2:86])=[O:85])[NH:33][C:31](=[O:32])[CH:30]([CH2:87][CH2:88][CH2:89][CH2:90][NH2:91])[NH:29][C:27](=[O:28])[CH:26]([NH:92][C:93]([CH2:95][NH:96][C:97]([CH:99]([NH2:101])[CH3:100])=[O:98])=[O:94])[CH2:25][S:24][S:23][CH2:22][CH:21]([C:102]([OH:104])=[O:103])[NH:20][C:18](=[O:19])[CH:17]([CH2:105][OH:106])[NH:16][C:14](=[O:15])[CH:13]([CH:107]([OH:109])[CH3:108])[NH:12][C:10](=[O:11])[CH:9]([CH2:110][C:111]2[CH:116]=[CH:115][CH:114]=[CH:113][CH:112]=2)[NH:8][C:6]1=[O:7]>>[CH3:3][C@@H:4]([OH:117])[C@@H:5]1[NH:53][C:51](=[O:52])[C@H:50]([CH2:54][CH2:55][CH2:56][CH2:57][NH2:58])[NH:49][C:47](=[O:48])[C@H:46]([CH2:59][C:60]2[C:68]3[CH:67]=[CH:66][CH:65]=[CH:64][C:63]=3[NH:62][CH:61]=2)[NH:45][C:43](=[O:44])[C@H:42]([CH2:69][C:70]2[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=2)[NH:41][C:39](=[O:40])[C@H:38]([CH2:76][C:77]2[CH:78]=[CH:79][CH:80]=[CH:81][CH:82]=2)[NH:37][C:35](=[O:36])[C@H:34]([CH2:83][C:84]([NH2:86])=[O:85])[NH:33][C:31](=[O:32])[C@H:30]([CH2:87][CH2:88][CH2:89][CH2:90][NH2:91])[NH:29][C:27](=[O:28])[C@@H:26]([NH:92][C:93]([CH2:95][NH:96][C:97]([C@@H:99]([NH2:101])[CH3:100])=[O:98])=[O:94])[CH2:25][S:24][S:23][CH2:22][C@@H:21]([C:102]([OH:104])=[O:103])[NH:20][C:18](=[O:19])[C@H:17]([CH2:105][OH:106])[NH:16][C:14](=[O:15])[C@H:13]([C@H:107]([OH:109])[CH3:108])[NH:12][C:10](=[O:11])[C@H:9]([CH2:110][C:111]2[CH:112]=[CH:113][CH:114]=[CH:115][CH:116]=2)[NH:8][C:6]1=[O:7]
Reactant: CC(N)C(=O)NCC(=O)NC1CSSCC(C(=O)O)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C(Cc2ccccc2)NC(=O)C(C(C)O)NC(=O)C(CCCCN)NC(=O)C(Cc2c[nH]c3ccccc23)NC(=O)C(Cc2ccccc2)NC(=O)C(Cc2ccccc2)NC(=O)C(CC(N)=O)NC(=O)C(CCCCN)NC1=O
Agent: [Cl-]
Agent: [Na+]
Product: C[C@H](N)C(=O)NCC(=O)N[C@H]1CSSC[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](Cc2ccccc2)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](Cc2c[nH]c3ccccc23)NC(=O)[C@H](Cc2ccccc2)NC(=O)[C@H](Cc2ccccc2)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCCCN)NC1=O

Procedure:
A pharmaceutical composition of somatostatin was prepared in the form of eye drops by adding 1 mL of 0.9% sodium chloride and 1.4% poly(vinyl alcohol) aqueous solution to 0.27 mg of somatostatin-14. Finally, the solution was filtered through a 0.22 μm sterilizing filter.
Reaction SMILES: [F:1][C:2]1[C:21]([NH2:22])=[C:6]2[CH2:7][S:8](=[O:20])(=[O:19])[N:9]([CH2:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[C:5]2=[CH:4][CH:3]=1.[Cl:23]N1C(=O)CCC1=O.CCOCC.O>CN(C)C=O>[Cl:23][C:4]1[CH:3]=[C:2]([F:1])[C:21]([NH2:22])=[C:6]2[C:5]=1[N:9]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=1)[S:8](=[O:20])(=[O:19])[CH2:7]2
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1ccc(CN2c3ccc(F)c(N)c3CS2(=O)=O)cc1
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CN2c3c(Cl)cc(F)c(N)c3CS2(=O)=O)cc1
Temperature: 80 °C
Yield: 93.4 %

Procedure:
A mixture of the title compound of Step C (0.387 g, 1.2 mmol) and N-chlorosuccinimide (0.168 g, 1.26 mmol) in dimethylformamide (6 mL) was heated at 80° C. for 4 h. After completion of the reaction, the mixture was poured into a mixture of ether (25 mL) and water (10 mL). The organic phase was separated, dried (MgSO4) and the solvent was removed on a rotary evaporator. Flash chromatography of the resulting residue afforded 0.4 g of the title compound of Step D. 1H NMR (CDCl3, 400 MHz): δ7.23 (d,2H), 7.03 (d,1H), 6.74 (d,2H), 4.93 (s,2H), 3.84 (s,2H), 3.75 (s,3H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH2:11][C:12]([OH:14])=O.[NH:15]1[CH2:21][CH2:20][CH2:19][C:18](=[O:22])[C:17]2[CH:23]=[CH:24][CH:25]=[CH:26][C:16]1=2>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH2:11][C:12]([N:15]1[CH2:21][CH2:20][CH2:19][C:18](=[O:22])[C:17]2[CH:23]=[CH:24][CH:25]=[CH:26][C:16]1=2)=[O:14]
Reactant: O=C(O)CSc1nc2ccccc2s1
Reactant: O=C1CCCNc2ccccc21
Product: O=C1CCCN(C(=O)CSc2nc3ccccc3s2)c2ccccc21
Yield: 29 %

Procedure:
The title compound was synthesized according to General Procedure B using 2-(benzo[d]thiazol-2-ylthio)acetic acid and 1,2,3,4-tetrahydrobenzo[b]azepin-5-one (5) to yield 37 (160 mg, 29%): MS (APCI): m/z 369 [M+H]+. Anal. Calcd. for C19H16N2O2S2: C, 61.93; H, 4.38; N, 7.60. Found: C, 61.72; H, 4.31; N, 7.40.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[C:13]([OH:19])(=O)[CH2:14][C:15]#[C:16][CH3:17].[NH2:20][C:21]1[CH2:27][N:26]=[C:25]([C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=2)[C:24]2[CH:35]=[C:36]([CH2:42][CH3:43])[C:37]([S:39][CH2:40][CH3:41])=[CH:38][C:23]=2[N:22]=1>O1CCCC1.CN(C)C=O>[CH2:40]([S:39][C:37]1[C:36]([CH2:42][CH3:43])=[CH:35][C:24]2[C:25]([C:28]3[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=3)=[N:26][CH2:27][C:21]3[N:22]([C:15]([CH2:16][CH3:17])=[CH:14][C:13](=[O:19])[N:20]=3)[C:23]=2[CH:38]=1)[CH3:41]
Reactant: CC#CCC(=O)O
Reactant: CCSc1cc2c(cc1CC)C(c1ccc(C)cc1)=NCC(N)=N2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCSc1cc2c(cc1CC)C(c1ccc(C)cc1)=NCc1nc(=O)cc(CC)n1-2

Procedure:
In the manner given in Example 16, carbonyldiimidazole, 3-pentynoic acid and 2-amino-8-ethylthio-7-ethyl-5-(p-methylphenyl)-3H-1,4-benzodiazepine were stirred in tetrahydrofuran-dimethylformamide to give 10-ethylthio 1,9-diethyl-7-(p-methylphenyl)pyrimido[1,2-a][1,4]benzodiazepin-3(5H)-one.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[CH2:3][CH2:4][NH:5][C:6]1[C:19]2[C:18](=[O:20])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[S:11][C:10]=2[C:9]([CH:21]=O)=[CH:8][CH:7]=1.[CH:24]([NH2:26])=[O:25].[OH-].[Na+]>C(O)=O>[CH3:1][N:2]([CH3:23])[CH2:3][CH2:4][NH:5][C:6]1[C:19]2[C:18](=[O:20])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[S:11][C:10]=2[C:9]([CH2:21][NH:26][CH:24]=[O:25])=[CH:8][CH:7]=1
Reactant: CN(C)CCNc1ccc(C=O)c2sc3ccccc3c(=O)c12
Reactant: NC=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Product: CN(C)CCNc1ccc(CNC=O)c2sc3ccccc3c(=O)c12
Temperature: 170 °C

Procedure:
A mixture of 1-[[2-(dimethylamino)ethyl]amino]-9-oxothioxanthen-4-carboxaldehyde (4.75 g), formamide (66.5 mL) and formic acid (7.6 mL) was heated at 170° C. for 4 hours. The mixture was poured into ice water (250 mL), basified with 35% NaOH and extracted with chloroform. The organic layer was washed with water (2X), then brine (1X) and the solvent was dried over Na2SO4 and concentrated in vacuo to afford 6.3 g of N-[[1-[[2-(dimethylamino)ethyl]amino]-9-oxothioxanthen-4-yl]methyl]formamide.