Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][C:10]([C:17]([F:20])([F:19])[F:18])=[N:9]2)=[CH:4][CH:3]=1.Cl[C:22]1[CH:27]=[C:26]([C:28]#[N:29])[CH:25]=[CH:24][N:23]=1>O1CCOCC1.C(OCC)(=O)C>[C:28]([C:26]1[CH:25]=[CH:24][N:23]=[C:22]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([N:8]3[C:12]([C:13]([F:14])([F:15])[F:16])=[CH:11][C:10]([C:17]([F:20])([F:19])[F:18])=[N:9]3)=[CH:6][CH:7]=2)[CH:27]=1)#[N:29]
Reactant: N#Cc1ccnc(Cl)c1
Reactant: Nc1ccc(-n2nc(C(F)(F)F)cc2C(F)(F)F)cc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: N#Cc1ccnc(Nc2ccc(-n3nc(C(F)(F)F)cc3C(F)(F)F)cc2)c1
Temperature: 125 °C
Yield: 54.8 %

Procedure:
A mixture of 1-(4′-aminophenyl)-3,5-bis(trifluoromethyl)pyrazole (0.36 g) and 2-chloro-4-cyanopyridine (0.14 g) in dioxane (1 mL) was heated at 125° C. in a sealed tube for 5 days. The mixture was diluted with ethyl acetate and washed with water. The organic phase was dried, filtered and evaporated. Chromatography of the residue over silica gel (methylene chloride to 2% ethanol/methylene chloride gradient gave the above-named compound (0.22 g) mp 152-153° C. NMR (CDCl3) 8.45 (1H, m), 7.86 (3H, m), 7.48 (2H, d), 7.20 (1H, br s), 7.07 (1H, s), 6.91 (1H, m).
Reaction SMILES: [C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][C:4]([CH2:7][S:8]([NH:11]CC2C=CC(OC)=CC=2OC)(=[O:10])=[O:9])=[CH:3][CH:2]=1.C([Li])CCC.[O:34]1[CH2:37][C:36](=[O:38])[CH2:35]1.FC(F)(F)C(O)=O>C1COCC1.CCCCCC>[C:1]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:2]=[CH:3][C:4]([CH:7]([C:36]2([OH:38])[CH2:37][O:34][CH2:35]2)[S:8]([NH2:11])(=[O:9])=[O:10])=[CH:5][CH:6]=1
Reactant: O=C1COC1
Reactant: COc1ccc(CNS(=O)(=O)Cc2ccc(-c3ccccc3)cc2)c(OC)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)C(c1ccc(-c2ccccc2)cc1)C1(O)COC1
Reaction time: 0.08 h

Procedure:
Under inert gas, 0.500 g of C-biphenyl-4-yl-N-(2,4-dimethoxybenzyl)methanesulfonamide was initially charged in 5 ml of THF and then, at −78° C., 1.8 ml of a 1.6 N butyllithium solution in hexane were added dropwise. The reaction mixture was stirred for 5 minutes and then admixed dropwise with 0.24 ml of 3-oxetanone. The mixture was stirred at constant temperature for 5 minutes, 0.28 ml of trifluoroacetic acid were added and the mixture was allowed to come to room temperature. The solvent was removed under reduced pressure. The residue was dissolved in 2 ml of dichloromethane, and 2 ml of trifluoroacetic acid were added. After stirring at room temperature for 60 minutes, 50 ml of saturated potassium carbonate solution were added and the mixture was extracted with dichloromethane, dried over magnesium sulfate and concentrated. The crude product was purified by means of normal phase chromatography using a Flashmaster with an n-heptane/ethyl acetate gradient. This gave the product (170 mg) with a molecular weight of 319.4 g/mol (C16H17NO4S).
Reaction SMILES: C(Cl)Cl.[C:4]([C:8]1[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1)([CH3:7])([CH3:6])[CH3:5].[C:15](=O)([O:26]C1C=CC([N+]([O-])=O)=CC=1)[O:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1>CN(C1C=CN=CC=1)C.CCCCCC.C(OC(=O)C)C>[C:15](=[O:26])([O:16][C:17]1[CH:18]=[CH:19][C:20]([N+:23]([O-:25])=[O:24])=[CH:21][CH:22]=1)[O:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([C:4]([CH3:7])([CH3:5])[CH3:6])[CH:9]=1
Reactant: CC(C)(C)c1cccc(O)c1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)Oc1ccc([N+](=O)[O-])cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cccc(OC(=O)Oc2ccc([N+](=O)[O-])cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.6 %

Procedure:
An oven-dried 25 mL flask was charged with dry CH2Cl2 (5 mL), 3-t-butylphenol (100 mg, 0.67 mmol), bis(4-nitrophenyl) carbonate (405 mg, 1.34 mmol) and 4-DMAP (162 mg, 1.34 mmol). The reaction was stirred overnight at room temperature and then evaporated. Column chromatography (n-hexane/ethylacetate 8:1) yielded 3-t-butylphenyl 4-nitrophenyl carbonate (189 mg, 0.60 mmol, 90%). This carbonate was dissolved in dry CH2Cl2 (8 mL) and 4-DMAP (162 mg, 1.34 mmol) was added. After 15 min, propargylamine (73 mg, 0.085 ml, 1.34 mmol) was added by syringe. The reaction was allowed to stir overnight at room temperature and then evaporated. Column chromatography (n-hexane/ethylacetate 15:1) yielded N-propargyl-3-t-butylphenyl carbamate (93 mg, 0.40 mmol, 60%). 1H NMR (CDCl3, 400 MHz) δ 1.32 (t, 9H), 2.30 (s, 1H), 4.08 (d, J=5.2 Hz, 2H), 5.27 (broad, 1H), 6.97 (d, J=7.2 Hz, 1H), 7.13 (d, J=2.0 Hz, 1H), 7.23˜7.31 (m, 2H); 13C NMR (CDCl3, 100 MHz) δ 30.9, 31.2, 34.7, 72.0, 79.3, 118.5, 122.5, 128.8, 150.6, 152.9, 154.2.
Reaction SMILES: [C:1]([S:5]([CH2:8][C@@H:9]1[CH2:14][C@H:13]([N:15]([CH:17]([CH3:19])[CH3:18])[CH3:16])[CH2:12][CH2:11][C@@H:10]1[N:20]1[CH2:24][CH2:23][C@H:22]([NH:25]C(=O)OCC2C=CC=CC=2)[C:21]1=[O:36])(=[O:7])=[O:6])([CH3:4])([CH3:3])[CH3:2].CCOCC>Br.CC(O)=O.CCOC(C)=O>[NH2:25][C@H:22]1[CH2:23][CH2:24][N:20]([C@H:10]2[CH2:11][CH2:12][C@@H:13]([N:15]([CH:17]([CH3:19])[CH3:18])[CH3:16])[CH2:14][C@H:9]2[CH2:8][S:5]([C:1]([CH3:2])([CH3:4])[CH3:3])(=[O:7])=[O:6])[C:21]1=[O:36]
Reactant: CC(C)N(C)[C@@H]1CC[C@H](N2CC[C@H](NC(=O)OCc3ccccc3)C2=O)[C@H](CS(=O)(=O)C(C)(C)C)C1
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(C)N(C)[C@@H]1CC[C@H](N2CC[C@H](N)C2=O)[C@H](CS(=O)(=O)C(C)(C)C)C1
Yield: 33.7 %

Procedure:
The material from above benzyl (S)-1-((1S,2R,4R)-2-(tert-butylsulfonylmethyl)-4-(isopropyl(methyl)amino)cyclohexyl)-2-oxopyrrolidin-3-ylcarbamate (1.0 g) was dissolved in 33% HBr/AcOH (5 mL) at rt. The solution was stirred for 30 min before Et2O was added. This resulted in a precipitate which was isolated. The solid was dissolved in EtOAc and was washed with sat. Na2CO3 solution. The organic phase was dried (MgSO4), filtered, and concentrated to afford (S)-3-amino-1-((1S,2R,4R)-2-(tert-butylsulfonylmethyl)-4-(isopropyl(methyl)amino)cyclohexyl)pyrrolidin-2-one (250 mg). MS found: (M+H)+=388.4.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4](F)[CH:3]=1.[NH:11]1[CH2:16][CH2:15][CH2:14][CH2:13]C1.CC(N(C)C)=O>CCOC(C)=O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([N:11]2[CH2:13][CH2:14][CH2:15][CH2:16]2)[CH:3]=1
Reactant: C1CCNCC1
Reactant: O=Cc1ccc(Br)cc1F
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: O=Cc1ccc(Br)cc1N1CCCC1
Temperature: 120 °C
Yield: 96679.6 %

Procedure:
A 20 mL screwtop vial was charged with 4-bromo-2-fluorobenzaldehyde (200 mg, 0.985 mmol), piperadine (116 μL, 1.19 mmol), and DMA (1 mL). The reaction was heated to 120° C. for 3 h. The reaction was diluted in EtOAc and extracted with brine (3×). The organics were dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was chromatographed on a silica gel column (0% to 20% EtOAc in hexanes) and yielded 4-bromo-2-(pyrrolidin-1-yl)benzaldehyde (242 g, 92%). 1H NMR 400 MHz (CDCl3) δ 10.21 (s, 1H), 7.66 (dd, J=8.3, 2.4 Hz, 1H), 7.31-7.17 (m, 2H), 4 (m, 4H), 1.78 (m, 4H), 1.71-1.60 (m, 2H). LCMS (ESI, m/z): 268 [M+H]+.
Reaction SMILES: C[Si](C)(C)[O:3][C:4]1[N:5]=[N:6][CH:7]=[C:8]([O:10][Si](C)(C)C)[N:9]=1.Br[CH2:18][CH2:19][CH2:20][CH2:21][Cl:22].CO>ClC(Cl)C.II>[Cl:22][CH2:21][CH2:20][CH2:19][CH2:18][N:5]1[C:4](=[O:3])[NH:9][C:8](=[O:10])[CH:7]=[N:6]1
Reactant: C[Si](C)(C)Oc1cnnc(O[Si](C)(C)C)n1
Reactant: ClCCCCBr
Agent: II
Solvent: CO
Solvent: CC(Cl)Cl
Product: O=c1cnn(CCCCCl)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 25 h
Yield: 76.5 %

Procedure:
22.1 g of 3,5-Bis-trimethylsilanyloxy-[1,2,4]triazine (86 mmol) were dissolved in 150 mL of dichloroethane followed by addition of 14.7 g of 1-bromo-4-chloro-butane (86 mmol) and 0.218 g of iodine (0.858 mmol). The reaction mixture was stirred for 25 h at room temperature. Then, 300 mL of methanol were added and the mixture was stirred for an additional 10 minutes. The solvents were evaporated under reduced pressure and the residue was partitioned between dichloromethane and water. The aqueous phase was extracted several times with dichloromethane. The combined organic layers were washed with 10% aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and the organic phase was evaporated under reduced pressure. The thus obtained crude product was purified via silica gel chromatography using dichloromethane-methanol 0-10% to yield 13.4 g of the desired product.
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[C:19]3[C:14](=[CH:15][C:16]([C:20]([N:22]4[CH2:27][CH2:26][N:25]([CH:28]([CH3:30])[CH3:29])[CH2:24][CH2:23]4)=[O:21])=[CH:17][CH:18]=3)[N:13](C)[CH:12]=2)[CH2:7][CH2:6]1)[CH:2]([CH3:4])[CH3:3].Cl.C(N1CC=C(C2C3C(=CC(C(N4CCN(C(C)C)CC4)=O)=CC=3)NC=2)CC1)C(C)C.[CH3:63][S:64](Cl)(=[O:66])=[O:65]>>[CH2:1]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[C:19]3[C:14](=[CH:15][C:16]([C:20]([N:22]4[CH2:27][CH2:26][N:25]([CH:28]([CH3:30])[CH3:29])[CH2:24][CH2:23]4)=[O:21])=[CH:17][CH:18]=3)[N:13]([S:64]([CH3:63])(=[O:66])=[O:65])[CH:12]=2)[CH2:7][CH2:6]1)[CH:2]([CH3:4])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)CN1CC=C(c2cn(C)c3cc(C(=O)N4CCN(C(C)C)CC4)ccc23)CC1
Agent: CC(C)CN1CC=C(c2c[nH]c3cc(C(=O)N4CCN(C(C)C)CC4)ccc23)CC1
Agent: Cl
Product: CC(C)CN1CC=C(c2cn(S(C)(=O)=O)c3cc(C(=O)N4CCN(C(C)C)CC4)ccc23)CC1

Procedure:
According to the procedure described for the synthesis of [3-(1-isobutyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1-methyl-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone; hydrochloride (example 42) the title compound was prepared from [3-(1-isobutyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone and methanesulfonylchloride (commercially available). MS (m/e): 487.3 (MH+).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:13])([CH3:12])[CH2:7][C:6]2([CH3:15])[CH3:14].[C:16]1([P:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[Cl-:1].[CH3:12][C:8]1([CH3:13])[C:9]2[C:5](=[CH:4][C:3]([CH2:2][P+:22]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:11][CH:10]=2)[C:6]([CH3:15])([CH3:14])[CH2:7]1
Reactant: CC1(C)CC(C)(C)c2cc(CCl)ccc21
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC1(C)CC(C)(C)c2cc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)ccc21
Product: [Cl-]

Procedure:
In a manner analogous to that described in Example 1, from 5-chloromethyl-1,1,3,3-tetramethyl-indane and triphenylphosphine there can be obtained [1-(1,1,3,3-tetramethyl-5-indanyl)methyl]-triphenylphosphonium chloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.[F:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16].O.O=[CH:22][C:23]([OH:25])=[O:24]>C(#N)C>[F:12][C:13]1[CH:14]=[C:15]([NH:16][CH:22]([C:6]2[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:23]([OH:25])=[O:24])[CH:17]=[CH:18][CH:19]=1
Reactant: COc1ccc(B(O)O)cn1
Reactant: O=CC(=O)O
Reactant: Nc1cccc(F)c1
Solvent: O
Solvent: CC#N
Product: COc1ccc(C(Nc2cccc(F)c2)C(=O)O)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.3 %

Procedure:
A mixture of 6-methoxypyridin-3-ylboronic acid (200 mg, 1.31 mmol), 3-fluoroaniline (126 μl, 1.31 mmol) and 2-oxoacetic acid hydrate (120 mg, 1.31 mmol) in acetonitrile (20 ml) was stirred at room temperature overnight. The solvent was evaporated, and the crude product was purified by flash-chromatography (DCM/MeOH=9/1) to obtain 2-(3-fluorophenylamino)-2-(6-methoxypyridin-3-yl)acetic acid (48 mg, 13.3% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH:15]=[CH:14][NH:13][C:7]=3[C:8](=[O:12])[NH:9][C:10]=2[CH:11]=1.C([C:18]([O-:20])=[O:19])C.[Cl:21][S:22](O)(=[O:24])=[O:23]>>[Cl:1][C:2]1[C:3]([S:22]([Cl:21])(=[O:24])=[O:23])=[CH:4][C:5]2[C:6]3[C:15]([C:18]([OH:20])=[O:19])=[CH:14][NH:13][C:7]=3[C:8](=[O:12])[NH:9][C:10]=2[CH:11]=1
Reactant: O=c1[nH]c2cc(Cl)ccc2c2cc[nH]c12
Reactant: CCC(=O)[O-]
Reactant: O=S(=O)(O)Cl
Product: O=C(O)c1c[nH]c2c(=O)[nH]c3cc(Cl)c(S(=O)(=O)Cl)cc3c12
Temperature: 90 °C
Yield: 90 %

Procedure:
In a sealed tube, 1.16 g (4 mmol) of 7-chloro-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate is dissolved in 5.3 mL (80 mmol) of chlorosulfonic acid. The reaction mixture is placed on an oil bath heated beforehand to 90° C. for 6 hours, cooled on an ice bath then poured slowly onto crushed ice. The solid is filtered, rinsed with water, diisopropyl ether and pentane then dried under vacuum to give 1.3 g (90%) of 7-chloro-8-chlorosulfonyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid in the form of a brown solid.
Reaction SMILES: [H-].[Na+].[CH:3](=[O:11])[C:4]1[C:5](=[CH:7][CH:8]=[CH:9][CH:10]=1)[OH:6].[CH2:12](Br)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>CN(C)C=O.CCCCCC>[CH2:22]([O:6][C:5]1[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=1[CH:3]=[O:11])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH3:12]
Reactant: O=Cc1ccccc1O
Reactant: CCCCCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CCCCCCCCCCCOc1ccccc1C=O

Procedure:
To a stirred suspension of sodium hydride (10.0 mmol), which was prewashed with petroleum ether, in sieve dried dimethylformamide (10 ml) was added dropwise a solution of salicylaldehyde (10.1 mmol) in dimethylformamide (1 ml)'. To the reaction mixture was then added undecyl bromide (10.0 mmol) and the mixture stirred for 16 hours at ambient temperature under nitrogen. The reaction mixture was taken up in hexane (50 ml) and washed with 10 percent sodium hydroxide (2×50 ml) and saturated sodium chloride (50 ml). The organic phase was dried over anhydrous magnesium sulfate and charcoal. Evaporation of the volatiles yielded a colorless liquid which was purified by flash chromatography over silica gel with 2 percent ethyl acetate in hexane as eluant to afford the desired product as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13]([O:15]C)=O)=[C:10]([N:17]=[CH:18][N:19]([CH3:21])C)[CH:9]=2)=[CH:4][CH:3]=1.Cl.NC[CH2:25][C:26]1[CH:38]=[CH:37][C:29]([CH2:30][N:31]2[CH2:35][CH2:34][CH2:33][C:32]2=[O:36])=[CH:28][CH:27]=1.C(N(CC)C(C)C)(C)C.C(O)C>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]3[C:13](=[O:15])[N:19]([CH2:21][CH2:25][C:26]4[CH:27]=[CH:28][C:29]([CH2:30][N:31]5[CH2:35][CH2:34][CH2:33][C:32]5=[O:36])=[CH:37][CH:38]=4)[CH:18]=[N:17][C:10]=3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: NCCc1ccc(CN2CCCC2=O)cc1
Reactant: COC(=O)c1sc(-c2ccc(Cl)cc2)cc1N=CN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C1CCCN1Cc1ccc(CCn2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)cc1
Temperature: 70 °C
Reaction time: 3 h
Yield: 75.8 %

Procedure:
A mixture of methyl 5-(4-chlorophenyl)-3-(dimethylaminomethyleneamino)thiophene-2-carboxylate (0.1 g), 1-[4-(2-aminoethyl)benzyl]pyrrolidin-2-one hydrochloride (87 mg), N,N-diisopropylethylamine (44 mg) and ethanol (2 ml) was stirred at 70° C. for 3 hr. The reaction mixture was allowed to cool, ethyl acetate was added, and the precipitate was collected by filtration to give the title compound (109 mg) as a colorless powder.
Reaction SMILES: [C:1]1([CH3:35])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([NH:10]/[N:11]=[CH:12]/[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:23]=[CH:22][N:21]([C:24]3[CH:29]=[CH:28][C:27]([O:30][C:31]([F:34])([F:33])[F:32])=[CH:26][CH:25]=3)[N:20]=2)=[CH:15][CH:14]=1)=[S:9].[CH2:36](N(CC)CC)C.Cl[CH2:44][C:45](=O)[CH3:46].O>CC(=O)CC>[CH3:35][C:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH3:36])[C:2]=1[N:7]1[C:45]([CH3:46])=[CH:44][S:9]/[C:8]/1=[N:10]/[N:11]=[CH:12]\[C:13]1[CH:14]=[CH:15][C:16]([C:19]2[N:23]=[CH:22][N:21]([C:24]3[CH:29]=[CH:28][C:27]([O:30][C:31]([F:32])([F:33])[F:34])=[CH:26][CH:25]=3)[N:20]=2)=[CH:17][CH:18]=1
Reactant: Cc1ccccc1NC(=S)N/N=C/c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: CC(=O)CCl
Reactant: CCN(CC)CC
Solvent: O
Solvent: CCC(C)=O
Product: Cc1cccc(C)c1-n1c(C)cs/c1=N/N=C\c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 75 °C
Yield: 80.3 %

Procedure:
To a solution of (E)-N-(o-tolyl)-2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzylidene)hydrazinecarbothioamide (257 mg, 0.520 mmol) in butanone (5 mL) was added triethylamine (0.14 mL, 1.0 mmol) and chloroacetone (0.06 mL, 0.73 mmol) and refluxed at 75° C. for 15 h. The mixture was allowed to cool to room temperature and then transferred to a separatory funnel containing water (5 mL) and extracted twice with dichloromethane. The organic layers were filtered through a phase separator, adsorbed onto silica gel, and purified by flash column chromatography to afford the title compound as a yellow solid (229 mg, 83%): mp 87° C. (dec); 1H NMR (400 MHz, CDCl3) δ 8.56 (s, 1H), 8.19-8.15 (m, 3H), 7.82-7.75 (m, 4H), 7.43-7.30 (m, 5H), 7.24 (d, J=7.3 Hz, 1H), 5.88 (d, J=1.3 Hz, 1H), 2.21 (s, 3H), 1.80 (d, J=1.2 Hz, 3H); ESIMS m/z 536 (M+H).
Reaction SMILES: Cl[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]=[C:4]([NH2:12])[N:3]=1.C(N(CC)CC)C.Cl.[CH2:21]([O:23][C:24](=[O:31])[CH:25]([CH2:27][CH:28]([CH3:30])[CH3:29])[NH2:26])[CH3:22]>C(O)CCC>[CH2:21]([O:23][C:24](=[O:31])[CH:25]([NH:26][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]=[C:4]([NH2:12])[N:3]=1)[CH2:27][CH:28]([CH3:29])[CH3:30])[CH3:22]
Reactant: CCOC(=O)C(N)CC(C)C
Reactant: Nc1nc(Cl)c2c(n1)CCCC2
Agent: Cl
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: CCOC(=O)C(CC(C)C)Nc1nc(N)nc2c1CCCC2

Procedure:
A mixture of 4-chloro-5,6,7,8-tetrahydroquinazoline-2-ylamine (117 mg, 0.64 mmol), triethylamine (259 mg, 2.56 mmol), dl-leucine ethyl ester hydrochloride (250 mg, 1.28 mmol) and n-butanol (2 ml) was reacted for 6 hours at 80-90° C. According to the post-treatment of Example 1, the object compound was obtained (104.3 mg, 72.1%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]([CH2:15][CH2:16][Cl:17])[P:5](Cl)([N:7]([CH2:11][CH2:12][Cl:13])[CH2:8][CH2:9][Cl:10])=[O:6].[CH2:18]([OH:21])[CH2:19][OH:20].CC(C)([O-])C.[K+].Cl>O.C(OC)(C)(C)C.O1CCCC1>[OH:20][CH2:19][CH2:18][O:21][P:5]([N:4]([CH2:3][CH2:2][Cl:1])[CH2:15][CH2:16][Cl:17])([N:7]([CH2:8][CH2:9][Cl:10])[CH2:11][CH2:12][Cl:13])=[O:6]
Reactant: OCCO
Reactant: O=P(Cl)(N(CCCl)CCCl)N(CCCl)CCCl
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: COC(C)(C)C
Product: O=P(OCCO)(N(CCCl)CCCl)N(CCCl)CCCl
Temperature: 0 °C

Procedure:
A 12-L, three-neck, round-bottom flask was equipped with an overhead mechanical stirrer, a thermometer and a nitrogen inlet/outlet bubbler. The flask was charged with N,N,N′,N′-tetrakis(2-chloroethyl)phosphorodiamidic chloride (979 g, 2.68 moles), 2, ethylene glycol (1.5 L, 26.8 moles), 4 and tetrahydrofuran (3 L). The stirrer was set to agitate at a moderate rate (to provide a clear red solution) and the mixture was cooled to 0° C. using an ice/water bath. To this cooled solution was added potassium tert-butoxide (362 g, 3.22 moles) over 20 minutes. The reaction mixture was then slowly warmed to room temperature and stirred for a total of 19 hours. A solution of hydrogen chloride in water (8 L, 1M) was introduced into the flask over 10 minutes. The organic fraction was collected and the aqueous fraction was extracted with ethyl acetate (2×4 L). The combined organic fractions were washed with saturated aqueous sodium chloride solution (1×4 L) and the solvents were removed under reduced pressure (30 mm Hg vacuum, final bath temperature at 50° C.) on a rotary evaporator to provide a dark reddish brown oil. This crude organic product was then dissolved with warm (40° C.) methyl tert-butyl ether (2 L) and allowed to cool to room temperature, stirring for a total of 14 hours. The resulting slurry was stirred for 30 minutes at 0° C. after which the precipitate was collected by vacuum filtration and washed with cold methyl tert-butyl ether (1 L). The combined filtrates were concentrated under reduced pressure (30 mmHg vacuum, final bath temperature at 50° C.) on a rotary evaporator to a volume of 500 mL and stirred for 30 minutes at 0° C. The resulting precipitate was collected by vacuum filtration and washed with cold methyl tert-butyl ether (200 mL). Two crops of solid product were then combined and dried overnight (30 mm Hg, 40° C.) to produce 2-hydroxyethyl-N,N,N′,N′-tetrakis(2-chloroethyl)phosphorodiamidate, 3, as a tan powder (526 gm, 50% yield). TLC analysis showed one spot (Rf0.62; methanol:chloroform 1:9). Melting point: 76-78° C.; IR (KBr) 3372, 2957, 1459, 1344, 1206, 1098, 1053, 929 cm−1; MS (CI, methane) m/z 391(MH+), 353, 339, 248, 106. A thermal analysis (DSC) showed two exothermic decomposition ranges of 164-179 and 222-231 C.
Reaction SMILES: [Br:1][C:2]1[C:6]2[CH:7]=[N:8][CH:9]=[CH:10][C:5]=2[NH:4][N:3]=1.[H-].[Na+].[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20](Cl)(=[O:22])=[O:21]>C1COCC1>[Br:1][C:2]1[C:6]2[CH:7]=[N:8][CH:9]=[CH:10][C:5]=2[N:4]([S:20]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[Cl:13])(=[O:22])=[O:21])[N:3]=1
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: Brc1n[nH]c2ccncc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1Cl)n1nc(Br)c2cnccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-bromo-1H-pyrazolo[4,3-c]pyridine (198 mg, 1,0 mmol) in 10 ml THF was added portion wise at 0° C. sodium hydride (101 mg, 4 mmol, 95%). After addition was complete, 2-chlorobenzenesulfonyl chloride (495 mg, 2.347 mmol) was added and the reaction mixture was stirred overnight at room temperature. The reaction mixture was quenched by the addition of water. The product was extracted into ethyl acetate and the organic layer was washed with brine. The organic solvent was evaporated under reduced pressure to give 3-bromo-1-(2-chlorophenylsulfonyl)-1H-pyrazolo[4,3-c]pyridine as a yellow oil. The product was used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:15][CH2:16][C:17]#[N:18])[C@@H:9]([C:11]([O:13][CH3:14])=[O:12])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.C(Cl)(Cl)Cl.[Pt]=O>[NH2:18][CH2:17][CH2:16][CH2:15][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[C@@H:9]([C:11]([O:13][CH3:14])=[O:12])[CH3:10]
Reactant: [H][H]
Reactant: COC(=O)[C@@H](C)N(CCC#N)C(=O)OC(C)(C)C
Agent: O=[Pt]
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@@H](C)N(CCCN)C(=O)OC(C)(C)C

Procedure:
To a solution of methyl N-(tert-butoxycarbonyl)-N-(2-cyanoethyl)-D-alaninate (1.5 g) in ethanol (80 mL) and chloroform (1.4 mL) was added platinum oxide (350 mg), and the reaction mixture was stirred over an atmosphere of hydrogen for 16 h. The mixture was filtered through Celite, and the Celite washed with methanol and dichloromethane. The filtrate was concentrated to give methyl N-(3-aminopropyl)-N-(tert-butoxycarbonyl)-D-alaninate as an oily residue.
Reaction SMILES: [C:1]([O:5][C:6]([N:8](C(OC(C)(C)C)=O)[C:9]1[CH:10]=[C:11]([C:16]([Br:19])=[CH:17][N:18]=1)[C:12](OC)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH3:27]>CO>[Br:19][C:16]1[C:11]([C:12](=[O:13])[NH2:27])=[CH:10][C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[N:18][CH:17]=1
Reactant: N
Reactant: COC(=O)c1cc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ncc1Br
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1cc(C(N)=O)c(Br)cn1
Temperature: 50 °C

Procedure:
A solution of methyl 2-(bis(tert-butoxycarbonyl)amino)-5-bromoisonicotinate (Intermediate 83, 100 g, 232 mmol) in 7 N ammonia in methanol (600 mL) was allowed to stir at 50° C. in a 1 L sealed tube overnight. The resulting mixture was evaporated to dryness and the crude product was directly used for the next step without further purification.