Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([CH2:19][NH:20][CH:21]([CH3:23])[CH3:22])[CH2:3][O:4][C:5]1[CH:18]=[CH:17][C:8]([C:9]([CH2:11][CH2:12][C:13]([NH:15]C)=[O:14])=O)=[CH:7][CH:6]=1.O.[NH2:25]N>C(O)(=O)C>[OH:1][CH:2]([CH2:19][NH:20][CH:21]([CH3:23])[CH3:22])[CH2:3][O:4][C:5]1[CH:18]=[CH:17][C:8]([C:9]2[CH2:11][CH2:12][C:13](=[O:14])[NH:15][N:25]=2)=[CH:7][CH:6]=1
Reactant: CNC(=O)CCC(=O)c1ccc(OCC(O)CNC(C)C)cc1
Reactant: NN
Solvent: CC(=O)O
Solvent: O
Product: CC(C)NCC(O)COc1ccc(C2=NNC(=O)CC2)cc1
Yield: 52.4 %

Procedure:
3-[4-(2-Hydroxy-3-isopropylaminopropoxy)benzoyl]-N-methylpropionamide (5g, 0.015 mole) in 50% aqueous acetic acid (50 ml) was treated with hydrazine hydrate (2.4 ml, 0.047 mole) and heated under reflux for one hour. After evaporation under reduced pressure, the residue was dissolved in water, neutralised with aqueous sodium bicarbonate and extracted with dichloromethane. Evaporation of the dried organic solution gave 6-[4-(2-hydroxy-3-isopropylaminopropoxy)phenyl]-4,5-dihydro-3(2H)-pyridazinone (2.4 g, 50%, m.p. 108°-115°C). Crystallisation from water gave the pure pyridazinone, m.p. 116.5°-118°C.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[CH2:3][CH2:4][N:5]1[C:21](=[O:22])[C:20]2[C:19]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([Cl:23])[CH:17]=4)[NH:12][C:11]=3[CH:10]=[CH:9][C:8]=2[C:6]1=[O:7].[H-].[Na+].S(OC)(O[CH3:31])(=O)=O>>[CH3:1][N:2]([CH3:24])[CH2:3][CH2:4][N:5]1[C:21](=[O:22])[C:20]2[C:19]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([Cl:23])[CH:17]=4)[N:12]([CH3:31])[C:11]=3[CH:10]=[CH:9][C:8]=2[C:6]1=[O:7]
Reactant: COS(=O)(=O)OC
Reactant: CN(C)CCN1C(=O)c2ccc3[nH]c4ccc(Cl)cc4c3c2C1=O
Agent: [H-]
Agent: [Na+]
Product: CN(C)CCN1C(=O)c2ccc3c(c2C1=O)c1cc(Cl)ccc1n3C
Yield: 60 %

Procedure:
400 mg of N-(2-dimethylaminoethyl)-6-chlorocarbazole-3,4-dicarboximide, 50 mg of 60% sodium hydride and 150 mg of dimethyl sulfate were subjected to the same reaction as in Example 3 (1) to obtain 250 mg (yield: 60%) of N-(2-dimethylaminoethyl)-6-chloro-9-methylcarbazole-3,4-dicarboximide as yellow crystals.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH:7]([CH3:15])[CH:8]([F:14])[C:9](OCC)=[O:10])([CH3:6])=[O:5])[CH3:2].[OH-].[NH4+:17]>C(O)C>[NH2:17][C:9](=[O:10])[CH:8]([F:14])[CH:7]([P:4]([CH3:6])(=[O:5])[O:3][CH2:1][CH3:2])[CH3:15]
Reactant: CCOC(=O)C(F)C(C)P(C)(=O)OCC
Reactant: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: CCOP(C)(=O)C(C)C(F)C(N)=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 91.7 %

Procedure:
To a solution of ethyl 3-[ethoxy(methyl)phosphoryl]-2-fluorobutanoate (3.0 g, 12.4 mmol) in ethanol (15 mL) was added concentrated ammonium hydroxide (14.8 M, 1.3 mL, 19 mmol). The solution was stirred for 24 h at room temperature and then at 50° C. for 2 hours. Another portion of concentrated ammonium hydroxide (14.8 M, 0.5 mL, 7 mmol) was added and the mixture was stirred at room temperature for three days and then evaporated to give 2.4 g (91%) of a diastereomeric mixture of ethyl 3-amino-2-fluoro-1-methyl-3-oxopropyl(methyl)phosphinate as a clear oil. 1H NMR (400 MHz, CDCl3) δ5.9-6.7 (m, 2H), 4.9-5.6 (m, 1H), 4.0-4.2 (m, 2H), 2.5-2.8 (m, 1H), 1.2-1.6 (m, 9H).
Reaction SMILES: [C:1]([O:7][C:8]1[CH:9]=[C:10]([CH2:21][CH2:22][NH:23][C:24]([C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)=[O:25])[CH:11]=[CH:12][C:13]=1[O:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH3:32][I:33]>CC(C)=O>[I-:33].[CH3:32][N+:28]1[CH:29]=[CH:30][CH:31]=[C:26]([C:24](=[O:25])[NH:23][CH2:22][CH2:21][C:10]2[CH:11]=[CH:12][C:13]([O:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])=[C:8]([O:7][C:1](=[O:6])[C:2]([CH3:3])([CH3:4])[CH3:5])[CH:9]=2)[CH:27]=1
Reactant: CI
Reactant: CC(C)(C)C(=O)Oc1ccc(CCNC(=O)c2cccnc2)cc1OC(=O)C(C)(C)C
Solvent: CC(C)=O
Product: C[n+]1cccc(C(=O)NCCc2ccc(OC(=O)C(C)(C)C)c(OC(=O)C(C)(C)C)c2)c1
Product: [I-]
Reaction time: 6 h

Procedure:
To a solution of 5.0 g (11.7 mmol) of compound 8c in 20 ml of acetone, 3.3 g (23.4 mmol) of methyl iodide were added and the mixture was refluxed under stirring for 6 hrs, then cooled. The orange crystalline solid which separated was filtered, washed with ether and crystallized for acetone/ether. Yield, 5.6 g (85%), m.p. 163°-165° C. U.V. (buffer pH 7.4) 270, 215 nm. NMR (DMSO-d6) δ 7.68-7.06 (ms, 7H, C5N4N+ +C6H3 +NH), 4.56 (s, 3H, --N+ --CH3), 3.42 (q, 2H, J=7 Hz, --N--CH2), 3.19 (t, 2H, J=7 Hz, CH2), 1.32 (s, 18H, 2 --C(CH3)3). Anal. Calcd for C25H33IN2O5 : C, 52.82; H, 5.85; N, 4.92. Found: C, 52.76; H, 5.87; N, 4.90.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[H][H]>[Pd].C1(C)C=CC=CC=1>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH:9]([OH:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=O)Cc1ccc(O)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: Cc1ccccc1
Product: CCOC(=O)C(O)Cc1ccc(O)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 98.1 %

Procedure:
10 g of ethyl 3-(4-hydroxyphenyl)pyruvate and 30 ml of toluene were charged to a pressure reactor to form a solution, and 0.25 g of 5% palladium on charcoal was added thereto. The atmosphere was displaced with hydrogen, and the mixture was stirred at 50° C. under a hydrogen pressure of 5 kg/cm2 for 1 hour. After completion of the reaction, the reaction mixture was filtered to remove the catalyst, and the filtrate was concentrated under reduced pressure to give 9.9 g of ethyl 3-(4-hydroxyphenyl)lactate as a colorless oily substance.
Reaction SMILES: [OH-].[Na+].[C:3]([CH2:6][N:7]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14][N:13]([CH2:19][C:20]([OH:22])=[O:21])[CH2:12][CH2:11][N:10]([CH2:23][C:24]([OH:26])=[O:25])[CH2:9][CH2:8]1)([OH:5])=[O:4].O1[CH2:29][CH:28]1[CH2:30][CH2:31][C:32]([OH:34])=[O:33].CC(O)C>O.C(O)CCC>[O:33]=[C:32]1[O:34][CH:28]([CH2:29][N:16]2[CH2:15][CH2:14][N:13]([CH2:19][C:20]([OH:22])=[O:21])[CH2:12][CH2:11][N:10]([CH2:23][C:24]([OH:26])=[O:25])[CH2:9][CH2:8][N:7]([CH2:6][C:3]([OH:5])=[O:4])[CH2:18][CH2:17]2)[CH2:30][CH2:31]1
Reactant: O=C(O)CCC1CO1
Reactant: O=C(O)CN1CCNCCN(CC(=O)O)CCN(CC(=O)O)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCO
Solvent: O
Solvent: CC(C)O
Product: O=C(O)CN1CCN(CC(=O)O)CCN(CC2CCC(=O)O2)CCN(CC(=O)O)CC1

Procedure:
8.3 g (207.6 mmol) of sodium hydroxide is added to 12.0 g (34.6 mmol) of 1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane (D03A) in 50 ml of water. A solution that consists of 5.02 g (43.25 mmol) of 3-oxiranylpropionic acid (Dakoji et al., J. Am. Chem. Soc., 1996, 10971-10979) in 50 ml of n-butanol/50 ml of 2-propanol is added in drops thereto, and the solution is heated for 24 hours to 80° C. The reaction solution is evaporated to the dry state in a vacuum, the residue is mixed with 300 ml of water, and a pH of 3 is set with 3N hydrochloric acid. Then, it is extracted three times with 200 ml each of n-butanol, the combined butanol phases are evaporated to the dry state in a vacuum, and the residue is purified by chromatography (RP-18; mobile solvent: gradient that consists of water/acetonitrile).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[CH:13]=[C:12]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][N:16]=2)[C:11]([Cl:24])=[CH:10][C:9]=1[F:25])([CH3:4])([CH3:3])[CH3:2].[Cl-].[Ca+2].[Cl-].C(O)C.O>CN1CCCC1=O>[C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[CH:13]=[C:12]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][N:16]=2)[C:11]([Cl:24])=[CH:10][C:9]=1[F:25])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(Oc2ccc([N+](=O)[O-])cn2)c(Cl)cc1F
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)Nc1cc(Oc2ccc(N)cn2)c(Cl)cc1F
Yield: 57.2 %

Procedure:
A mixture of tert-butyl{4-chloro-2-fluoro-5-[(5-nitropyridin-2-yl)oxy]phenyl}carbamate (4.66 g, 12.1 mmol), reduced iron (61.2 mmol), calcium chloride (680 mg, 6.13 mmol) and ethanol (90 mL)/water (10 mL)/1-methyl-2-pyrrolidone (40 mL) was stirred with heating under reflux for 5 hr. Reduced iron (5.00 g, 89.5 mmol) and calcium chloride (700 mg, 6.31 mmol) were further added, and the mixture was stirred with heating under reflux for 16 hr. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was diluted with ethyl acetate (300 mL), washed with water (100 mL×2) and saturated brine (50 mL). The obtained organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=90/10→10/90), and fractions containing the object product were concentrated under reduced pressure to give the title compound (2.45 g, 57%) as a yellow powder.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([CH3:12])[N:11]=1)[C:6]([OH:8])=O)[CH3:2].[CH3:13][C:14]1([CH3:28])[CH:16]2[CH2:17][C:18]3[C:22]([CH:15]12)=[C:21]([CH3:23])[S:20][C:19]=3[C:24]([NH:26][NH2:27])=[O:25].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl>[CH3:13][C:14]1([CH3:28])[CH:16]2[CH2:17][C:18]3[C:22]([CH:15]12)=[C:21]([CH3:23])[S:20][C:19]=3[C:24]([NH:26][NH:27][C:6](=[O:8])[C:5]1[CH:9]=[C:10]([CH3:12])[N:11]=[C:3]([CH2:1][CH3:2])[CH:4]=1)=[O:25]
Reactant: CCc1cc(C(=O)O)cc(C)n1
Reactant: Cc1sc(C(=O)NN)c2c1C1C(C2)C1(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: CCc1cc(C(=O)NNC(=O)c2sc(C)c3c2CC2C3C2(C)C)cc(C)n1
Reaction time: 15 h
Yield: 172.2 %

Procedure:
To a mixture of 2-ethyl-6-methyl-isonicotinic acid (87.9 mg, 0.53 mmol), 1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid hydrazide (141.8 mg, 0.6 mmol), HOBt (100 mg, 0.74 mmol) and TEA (0.42 mL) in DCM (5 mL) is added at 0° C. EDC (200 mg, 0.78 mmol). The mixture is stirred for 15 h during which time it warmed from 0° C. to rt. The mixture is quenched with EA (50 mL) and washed with 1M aq. NaOH (2×10 mL). The organic phase is dried (Na2SO4), filtered and evaporated to give crude 2-ethyl-6-methyl-isonicotinic acid N′-(1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carbonyl)-hydrazide (350 mg); LC-MS: tR=0.80 min, [M+1]=384.34.
Reaction SMILES: [C:1]1([CH2:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]=2[O:18][CH3:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:20](=O)(=[O:23])([OH:22])[OH:21].O.C(=O)(O)[O-].[Na+]>CCCCCC.C(OCC)(=O)C.C(OCC)(=O)C>[CH3:19][O:18][C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:16]([S:20]([OH:23])(=[O:22])=[O:21])=[CH:17][C:8]=1[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(O)O
Reactant: COc1c(Cc2ccccc2)ccc2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1c(Cc2ccccc2)cc(S(=O)(=O)O)c2ccccc12
Reaction time: 2 h
Yield: 52 %

Procedure:
The product of Example 94 Part A (3.0 g, 0.012 mole) was added in portions to concentrated sulfuric acid (10 ml) at -10°. The mixture was stirred at -10° for 2 hours and poured into water. Sodium bicarbonate (1.0 g) was added, and the crude product was isolated by extraction with ethyl acetate. The title compound (2.0 g, 52%) was obtained as a brown oil after chromatography (1:1 hexane/ethyl acetate; then 99:1 ethyl acetate/acetic acid; then methanol).
Reaction SMILES: P(Br)(Br)[Br:2].[CH3:5][C:6]1[CH:20]=[CH:19][C:9]([S:10][C:11]2[CH:18]=[CH:17][C:14]([CH2:15]O)=[CH:13][CH:12]=2)=[CH:8][CH:7]=1>CCOCC>[CH3:5][C:6]1[CH:20]=[CH:19][C:9]([S:10][C:11]2[CH:18]=[CH:17][C:14]([CH2:15][Br:2])=[CH:13][CH:12]=2)=[CH:8][CH:7]=1
Reactant: BrP(Br)Br
Reactant: Cc1ccc(Sc2ccc(CO)cc2)cc1
Solvent: CCOCC
Product: Cc1ccc(Sc2ccc(CBr)cc2)cc1
Temperature: 0 °C
Reaction time: 12 h
Yield: 183.9 %

Procedure:
To a stirred mixture of phosphorus tribromide (1.20 g, 4.43 mM) and dry ether (100 ml) was added a solution (20 ml) of 4-(4-methylthiophenoxy)benzyl alcohol (3.00 g, 12.1 mM) in dry ether at the room temperature, and the mixture was stirred for 12 h at the same temperature. The mixture was poured into ice water, and the mixture was extracted with ether. The extract was washed with saturated sodium hydrogen carbonate solution and brine, dried with magnesium sulfate, and concentrated in vacuo to give 4-(4-methylthiophenoxy)benzyl bromide (2.39 g, 64%) as colorless crystals, m.p. 32.9° C.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([NH2:19])[CH2:15][CH2:14]2)[CH2:3][CH2:2]1.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26](O)=[O:27])[CH:21]=1.C(OC(Cl)=O)C(C)C>>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([NH:19][C:26]([C:22]3[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=3)=[O:27])[CH2:15][CH2:14]2)[CH2:3][CH2:2]1
Reactant: O=C(O)c1cccnc1
Reactant: NC1CCN(CCC2CCOc3ccccc32)CC1
Agent: CC(C)COC(=O)Cl
Product: O=C(NC1CCN(CCC2CCOc3ccccc32)CC1)c1cccnc1
Yield: 15 %

Procedure:
N-[1-[2-(3,4-dihydro-2H-1-benzopyran-4-yl)ethyl]-4-aminopiperidine was coupled to pyridine-3-carboxylic acid utilizing the isobutylchloroformate protocol described in Example 6. The resulting residue was further purified by chromatography on silica (eluant: chloroform/ethanol/ammonium hydroxide; 85/14/1) and crystallization from diethyl ether to afford the title compound (15% yield), mp=126-8°, Anal: C22H27N3O2 0.25 H2O, Calc. C, 71.42; H, 7.49; N, 11.36; Found: C, 71.25; H, 7.50; N, 11.19.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10]CC)=[O:9].[CH:18]([N:31]1[C:39]2[C:34](=[CH:35][C:36](/[C:40](/[CH3:45])=[CH:41]/[C:42](O)=[O:43])=[CH:37][CH:38]=2)[CH:33]=[CH:32]1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH:18]([N:31]1[C:39]2[C:34](=[CH:35][C:36](/[C:40](/[CH3:45])=[CH:41]/[C:42]([NH:1][C:2]3[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:3]=3[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:43])=[CH:37][CH:38]=2)[CH:33]=[CH:32]1)([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCOC(=O)CCCOc1ccc(C)cc1N
Reactant: C/C(=C\C(=O)O)c1ccc2c(ccn2C(c2ccccc2)c2ccccc2)c1
Product: C/C(=C\C(=O)Nc1cc(C)ccc1OCCCC(=O)O)c1ccc2c(ccn2C(c2ccccc2)c2ccccc2)c1

Procedure:
305 mg of compound 49 was obtained in a similar manner to those described in the Examples 1 and 2 using 558 mg of ethyl 4-(2-amino-4-methylphenoxy)butyrate and 455 mg of 3-(1-benzhydrylindol-5-yl)isocrotonic acid obtained according to the procedures described in the Reference Examples 1-4.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[CH:6][C:5]=12.[I:12]N1C(=O)CCC1=O.CN(C=O)C>C(OCC)(=O)C.C1COCC1.S([O-])([O-])(=O)=S.[Na+].[Na+]>[I:12][C:3]1[N:4]2[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[CH:6][C:5]2=[N:1][CH:2]=1
Reactant: N#Cc1ccn2ccnc2c1
Reactant: O=C1CCC(=O)N1I
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: N#Cc1ccn2c(I)cnc2c1
Reaction time: 2 h

Procedure:
In a 50 mL round-bottomed flask, imidazo[1,2-a]pyridine-7-carbonitrile (1.1 g, 7.68 mmol) and N-iodosuccinimide (2.07 g, 9.22 mmol) were combined with DMF (50 ml) to give a colorless solution. The reaction mixture kept at 20° C. and stirred for 2 h. The reaction mixture was diluted with ethyl acetate (150 ml), THF (50 ml) and 300 ml of 5% sodium thiosulfate and well shaken. The aqueous layer was back-extracted with ethyl acetate (1×100 mL). The organic layers were combined, washed with water, brine, dried (MgSO4) and evaporated. The crude material was purified by flash chromatography (silica gel, 60% to 80% ethyl acetate/hexanes) to give 3-iodo-imidazo[1,2-a]pyridine-7-carbonitrile. 1H NMR (300 MHz, DMSO-d6) δ: 8.52 (d, 1H) 8.44 (d, 1H) 8.04 (d, 1H) 7.36 (dd, 1H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:13]=[CH:12]2.[CH2:24]([NH:26][CH2:27][CH3:28])[CH3:25]>>[CH2:24]([N:26]([CH2:27][CH3:28])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:13]=[CH:12]2)[CH3:25]
Reactant: CCNCC
Reactant: BrCCCCCCOc1ccc2c(ccn2-c2ccccc2)c1
Product: CCN(CC)CCCCCCOc1ccc2c(ccn2-c2ccccc2)c1

Procedure:
In analogy to example 4.4, 5-(6-Bromo-hexyloxy)-1-phenyl-1H-indole and diethylamine were converted to yield Diethyl-[6-(1-phenyl-1H-indol-5-yloxy)-hexyl]-amine as colorless oil, MS: 365 (MH+).
Reaction SMILES: [N:1]1([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:35][CH2:34][CH2:33][C@H:2]1[C:3]([NH:5][C@H:6]([C:14]([N:16]([CH3:32])[C@H:17]([C:25]([NH:27][CH2:28][C:29]([OH:31])=O)=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].[NH2:43][C@H:44]([C:50]([NH:52][C@H:53]([C:58]([NH2:60])=[O:59])[CH2:54][CH2:55][S:56][CH3:57])=[O:51])[CH2:45][CH2:46][CH:47](C)C.Cl.[CH:62]1(N=C=NC2CCCCC2)CCCCC1.ON1C(=O)CCC1=O>>[N:1]1([C:36]([O:38][C:39]([CH3:40])([CH3:41])[CH3:42])=[O:37])[CH2:35][CH2:34][CH2:33][C@H:2]1[C:3]([NH:5][C@H:6]([C:14]([N:16]([CH3:32])[C@H:17]([C:25]([NH:27][CH2:28][C:29]([NH:43][C@H:44]([C:50]([NH:52][C@H:53]([C:58]([NH2:60])=[O:59])[CH2:54][CH2:55][S:56][CH3:57])=[O:51])[CH2:45][CH:46]([CH3:47])[CH3:62])=[O:31])=[O:26])[CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:15])[CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:4]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CN(C(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)[C@@H](Cc1ccccc1)C(=O)NCC(=O)O
Reactant: CSCC[C@H](NC(=O)[C@@H](N)CCC(C)C)C(N)=O
Agent: Cl
Agent: O=C1CCC(=O)N1O
Product: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](Cc1ccccc1)N(C)C(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C(N)=O
Yield: 100 %

Procedure:
Condensation of BocPro-Phe-MePhe-GlyOH (0.76 g.) and HLeu-MetNH2 hydrochloride salt (Example 1, 0.39 g.) using dicyclohexylcarbodiimide and N-hydroxysuccinimide gave BocPro-Phe-MePhe-Gly-Leu-MetNH2 in 100% yield. De-t-butoxycarbonylation of BocPro-Phe-MePhe-Gly-Leu-MetNH2 (1.07 g.) using hydrogen chloride in acetic acid gave HPro-Phe-MePhe-Gly-Leu-MetNH2, which was isolated as the amorphous white solid phosphate (1:1) salt dihydrate in 22% yield.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[S:3][C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1.[C:18](#[N:21])[CH:19]=[CH2:20].[OH-].C([N+](C)(C)C)C1C=CC=CC=1.C(OCC)C>CO>[C:18]([CH2:19][CH2:20][N:13]1[CH2:12][CH2:11][N:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([S:3][C:2]([F:1])([F:16])[F:17])[CH:5]=2)[CH2:15][CH2:14]1)#[N:21]
Reactant: C=CC#N
Reactant: FC(F)(F)Sc1cccc(N2CCNCC2)c1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: CCOCC
Solvent: CO
Product: N#CCCN1CCN(c2cccc(SC(F)(F)F)c2)CC1
Reaction time: 48 h
Yield: 84.7 %

Procedure:
N-(m-trifluoromethylthiophenyl)-piperazine (10.8 g, 0.047 g.mol.) and acrylonitrile (4.9 g, 0.094 g. mol.) are introduced into a 50 ml round bottomed flask provided with a stirrer and a reflux condenser. 0.1 ml of a 40% solution of benzyltrimethylammonium hydroxide in methyl alcohol is added with cooling and stirring. The mixture is allowed to stand at ambient temperature for 2 days and then heated for 2 hours to 80° C. After cooling, anhydrous diethyl ether (100 ml) is added to the reaction mixture, insoluble materials are filtered off, and the solution obtained evaporated on a water-bath in vacuo. The residue is fractionally distilled and N-(β-cyano-ethyl)-N'-(m-trifluoromethylthiophenyl)-piperazine (11 g, 88% yield) is thus obtained as a clear yellow viscous liquid, b.p. 198°-200°/3 mm Hg, nD23 = 1.5378.
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH2:19][C:20]([NH:22][CH3:23])=[O:21])[CH:16]=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.[CH3:26][C:27]([OH:44])([CH3:43])[CH2:28][N:29]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[N:30]1>[Pd]>[OH:44][C:27]([CH3:43])([CH3:26])[CH2:28][N:29]1[CH:33]=[C:32]([C:2]2[CH:25]=[CH:24][C:5]3[C:6]4[N:7]=[C:8]([C:14]5[N:15]([CH2:19][C:20]([NH:22][CH3:23])=[O:21])[CH:16]=[CH:17][N:18]=5)[S:9][C:10]=4[CH2:11][CH2:12][O:13][C:4]=3[CH:3]=2)[CH:31]=[N:30]1
Reactant: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CNC(=O)Cn1ccnc1-c1nc2c(s1)CCOc1cc(Br)ccc1-2
Agent: [Pd]
Product: CNC(=O)Cn1ccnc1-c1nc2c(s1)CCOc1cc(-c3cnn(CC(C)(C)O)c3)ccc1-2

Procedure:
Following the procedure for 355, 2-[2-(8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-imidazol-1-yl]-N-methyl-acetamide and 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol were reacted under Suzuki palladium conditions to give 405 MS: (ESI+)=497.2. 1H NMR (400 MHz, DMSO) δ 8.32 (d, J=8.3 Hz, 1H), 8.15 (s, 1H), 7.93 (s, OH), 7.38 (d, J=0.8 Hz, 1H), 7.32 (dd, J=8.3, 1.8 Hz, 1H), 7.25 (d, J=1.7 Hz, 1H), 7.05 (d, J=0.8 Hz, OH), 5.23 (s, 1H), 4.72 (s, 1H), 4.34 (t, J=5.0 Hz, 1H), 4.04 (s, 1H), 2.66 (t, J=4.4 Hz, 2H), 1.08 (s, 6H)
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[NH2:13][C:14]1[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17].C(N(CC)CC)C.[NH2:31][CH2:32][CH:33]1[O:39][CH2:38][CH2:37][N:36]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:35][CH:34]1[C:47]1[CH:52]=[CH:51][C:50]([Cl:53])=[C:49]([Cl:54])[CH:48]=1>C1(C)C=CC=CC=1.O>[Cl:54][C:49]1[CH:48]=[C:47]([CH:34]2[CH:33]([CH2:32][NH:31][C:2](=[O:4])[NH:13][C:14]3[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=3[C:16]([O:18][CH3:19])=[O:17])[O:39][CH2:38][CH2:37][N:36]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:35]2)[CH:52]=[CH:51][C:50]=1[Cl:53]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COC(=O)c1ccccc1N
Reactant: CC(C)(C)OC(=O)N1CCOC(CN)C(c2ccc(Cl)c(Cl)c2)C1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1ccccc1NC(=O)NCC1OCCN(C(=O)OC(C)(C)C)CC1c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 107.4 %

Procedure:
Triphosgene (95 mg) was added to a solution of methyl 2-aminobenzoate (120 mg) and triethylamine (0.17 mL) in toluene (5 mL), and the mixture was stirred at 0° C. for 30 min. To the reaction mixture were added tert-butyl (6SR,7RS)-7-(aminomethyl)-6-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (300 mg) and triethylamine (0.17 mL), and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (190 mg).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][C:9](I)=[N:8][C:6]=2[N:7]=1.[CH3:18][S:19]([C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1)(=[O:21])=[O:20].C(=O)([O-])[O-].[Na+].[Na+].[C:37](#[N:39])[CH3:38]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH3:18][S:19]([C:22]1[CH:23]=[C:24]([C:9]2[S:10][C:5]3[C:4]([N:12]4[CH2:17][CH2:16][O:15][CH2:14][CH2:13]4)=[N:3][C:2]([C:38]4[CH:37]=[N:39][C:2]([NH2:7])=[N:3][CH:4]=4)=[N:7][C:6]=3[N:8]=2)[CH:25]=[CH:26][CH:27]=1)(=[O:21])=[O:20]
Reactant: Clc1nc(N2CCOCC2)c2sc(I)nc2n1
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Reactant: CC#N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CS(=O)(=O)c1cccc(-c2nc3nc(-c4cnc(N)nc4)nc(N4CCOCC4)c3s2)c1

Procedure:
5-Chloro-2-iodo-7-morpholinothiazolo[4,5-d]pyrimidine, 3-(methylsulfonyl)phenyl boronic acid and trans-dichlorobis(triphenylphosphine)palladium(II) (0.1 eq) were slurried with equal parts 1M sodium carbonate (3 eq) and acetonitrile. The solution was microwaved at 90° C. for 10 minutes. Water was added and the solution was filtered. The aqueous layer was dried and combined with 5-pyrimidine-2-amine boronic acid (1.2 eq), and trans-dichlorobis(triphenylphosphine)palladium(II) (0.1 eq) were slurried with equal parts 1M sodium carbonate aqueous solution (3 eq) and acetonitrile. The solution was microwaved at 150° C. for 10 minutes. Water was added and the solution was filtered. The resulting precipitate was purified by reverse phase silica gel chromatography to yield 142.