Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]2[C:15]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[CH:14][NH:13][C:12](=[O:22])[CH:11]=2)[CH:3]=1.CC(C)([O-])C.CC(C)([O-])C.[Mg+2].CC(C)([O-])C.[K+].Br[CH:41]([CH3:45])[C:42]([OH:44])=[O:43]>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]2[C:15]([O:16][CH2:17][C:18]([F:19])([F:20])[F:21])=[CH:14][N:13]([CH:41]([CH3:45])[C:42]([OH:44])=[O:43])[C:12](=[O:22])[CH:11]=2)[CH:3]=1
Reactant: CC(Br)C(=O)O
Reactant: N#Cc1ccc(Cl)cc1-c1cc(=O)[nH]cc1OCC(F)(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [Mg+2]
Product: CC(C(=O)O)n1cc(OCC(F)(F)F)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
140 mg (purity 87%, 0.37 mmol) of 4-chloro-2-[2-oxo-5-(2,2,2-trifluoroethoxy)-1,2-dihydropyridin-4-yl]benzonitrile, 2.0 eq. of magnesium di-tert-butoxide, 1.05 eq. of potassium tert-butoxide and 1.5 eq. of 2-bromopropanoic acid (racemate) were reacted according to General Method 4A at 50° C. and, after aqueous work-up, used without purification for the next step. Yield: 214 mg (purity 73%, quant.)
Reaction SMILES: [Si]([O:18][CH2:19][CH2:20][N:21]1[C:25]([NH:26][C:27](=[O:44])[C@@H:28]([NH:37][CH2:38][C:39]2[N:40]=[CH:41][S:42][CH:43]=2)[CH2:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)=[CH:24][C:23]([C:45]2[CH:50]=[CH:49][N:48]=[C:47]([NH:51][CH3:52])[CH:46]=2)=[N:22]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[F:36][C:33]1[CH:32]=[CH:31][C:30]([CH2:29][C@H:28]([NH:37][CH2:38][C:39]2[N:40]=[CH:41][S:42][CH:43]=2)[C:27]([NH:26][C:25]2[N:21]([CH2:20][CH2:19][OH:18])[N:22]=[C:23]([C:45]3[CH:50]=[CH:49][N:48]=[C:47]([NH:51][CH3:52])[CH:46]=3)[CH:24]=2)=[O:44])=[CH:35][CH:34]=1
Reactant: CNc1cc(-c2cc(NC(=O)[C@H](Cc3ccc(F)cc3)NCc3cscn3)n(CCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)n2)ccn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CNc1cc(-c2cc(NC(=O)[C@H](Cc3ccc(F)cc3)NCc3cscn3)n(CCO)n2)ccn1
Reaction time: 2 h
Yield: 43 %

Procedure:
To a flask with 30.C (110 mg, 0.15 mmol) was added THF 1.2 mL, and 0.2 mL TBAF (1M, 0.3 mmol). After 2 hours, the reaction was concentrated and worked up with water and 30% isopropanol in chloroform. The organic phase was washed with water and brine, dried and concentrated. Reverse phase HPLC purification 5-40% afforded product 30 (32 mg, 43%). 1H NMR (400 MHz, MeOH) δ ppm 8.93 (d, J=1.96 Hz, 1H) 7.94 (d, J=5.48 Hz, 1H) 7.39 (d, J=1.96 Hz, 1H) 7.23 (dd, J=8.61, 5.48 Hz, 2H) 6.98-7.05 (m, 2H) 6.93-6.97 (m, 1H) 6.89 (s, 1H) 6.76 (s, 1H) 4.12 (td, J=5.09, 1.96 Hz, 2H) 3.84-4.01 (m, 4H) 3.57 (dd, J=7.82, 5.87 Hz, 1H) 3.10 (dd, J=13.69, 7.80 Hz, 1H) 2.95 (dd, J=13.69, 7.83 Hz, 1H) 2.91 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[N:13][C:5]2[NH:6][C:7]3[CH2:12][CH2:11][NH:10][CH2:9][C:8]=3[C:4]=2[CH:3]=1.CCN(C(C)C)C(C)C.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]=[C:33]=[O:34])=[CH:28][CH:27]=1.Cl.CCOCC>C(Cl)Cl.CCOCC>[ClH:1].[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]([N:10]2[CH2:11][CH2:12][C:7]3[NH:6][C:5]4[N:13]=[CH:14][C:2]([Cl:1])=[CH:3][C:4]=4[C:8]=3[CH2:9]2)=[O:34])=[CH:28][CH:27]=1
Reactant: COc1ccc(N=C=O)cc1
Reactant: Clc1cnc2[nH]c3c(c2c1)CNCC3
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: COc1ccc(NC(=O)N2CCc3[nH]c4ncc(Cl)cc4c3C2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.8 %

Procedure:
3-Chloro-6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;3′,4′-d]pyrrole (50 mg, 0.24 mmol), and DIEA (0.04 mL, 0.24 mmol) were dissolved in DCM (2 mL). 4-Methoxyphenyl isocyanate (0.03 mL, 0.26 mmol) was added dropwise, and the reaction solution was stirred overnight at room temperature. The crude reaction mixture was concentrated, and converted to the HCl salt by dissolving the crude material in MeOH (2 ml) and adding 1 M HCl/ether (2 equiv). The resulting solution was refrigerated overnight. Additional ether was added to drive precipitate formation. The resulting precipitate was filtered and dried under vacuum to provide 27 (15 mg, 16% yield) as a yellow solid. LC-MS (M+H=359, obsd.=359).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][N:6]=[C:5]2[Cl:13].[N:14]1([CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>CC(N(C)C)=O.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:13][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([N:25]3[CH2:24][CH2:23][N:22]([CH2:21][CH2:20][N:14]4[CH2:15][CH2:16][O:17][CH2:18][CH2:19]4)[CH2:27][CH2:26]3)[CH:3]=2)[C:8](=[O:12])[NH:7][N:6]=1
Reactant: C1CN(CCN2CCOCC2)CCN1
Reactant: O=c1[nH]nc(Cl)c2cc(Br)ccc12
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: O=c1[nH]nc(Cl)c2cc(N3CCN(CCN4CCOCC4)CC3)ccc12
Yield: 19.7 %

Procedure:
A mixture 6-bromo-4-chloro-2H-phthalazin-1-one (150 mg, 0.578 mmol), 1-[2-(morpholin-4-yl)ethyl]piperazine (127 mg, 0.636 mmol), Pd2(dba)3 (53 mg, 0.0578 mmol), rac-BINAP (108 mg, 0.173 mmol) and NaOtBu (139 mg, 1.445 mmol) in DMA (5 mL) was heated at 85° C. for 2 h. The mixture was allowed to cool, diluted with EtOAc and washed with water. The organic layer was washed with sat.aq. NaHCO3, brine and dried (Na2SO4). Preparatory HPLC afforded 4-chloro-6-[4-(2-morpholin-4-yl-ethyl)-piperazin-1-yl]-2H-phthalazin-1-one hydroformate (43 mg) as an orange solid, 1H (400 MHz, d6-DMSO) δ: 2.39 (m, 4H), 2.45 (m, 4H), 2.56 (m, 4H), 3.41 (m, 4H), 3.55 (t, 4H), 7.08 (d, 1H), 7.54 (dd, 1H), 8.03 (d, 1H), 8.15 (s, 1H), 12.49 (s, 1H) ppm; m/z (M+1) 378.05.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[C:14]([CH3:16])([CH3:15])[C:13]2[C:12]([F:17])=[C:11]([NH:18][C@@H:19]3[CH2:24][CH2:23][CH2:22][CH2:21][C@@H:20]3[NH:25]C(=O)OC(C)(C)C)[N:10]=[C:9]([C:33]3[CH:34]=[N:35][N:36]([CH3:38])[CH:37]=3)[C:8]=2[C:7]1=[O:39].[C:46]([OH:52])([C:48]([F:51])([F:50])[F:49])=[O:47]>>[NH2:25][C@H:20]1[CH2:21][CH2:22][CH2:23][CH2:24][C@H:19]1[NH:18][C:11]1[N:10]=[C:9]([C:33]2[CH:34]=[N:35][N:36]([CH3:38])[CH:37]=2)[C:8]2[C:7](=[O:39])[NH:6][C:14]([CH3:16])([CH3:15])[C:13]=2[C:12]=1[F:17].[C:46]([OH:52])([C:48]([F:51])([F:50])[F:49])=[O:47]
Reactant: COc1ccc(CN2C(=O)c3c(-c4cnn(C)c4)nc(N[C@@H]4CCCC[C@@H]4NC(=O)OC(C)(C)C)c(F)c3C2(C)C)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Product: Cn1cc(-c2nc(N[C@@H]3CCCC[C@@H]3N)c(F)c3c2C(=O)NC3(C)C)cn1

Procedure:
A solution of tert-butyl (1S,2R)-2-(2-(2,4-dimethoxybenzyl)-7-fluoro-1,1-dimethyl-4-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)cyclohexylcarbamate (5 mg, 9.57 μmol) in TFA (1 mL) was heated at 60° C. for 0.5 h. The reaction mixture was subsequently purified by preparative HPLC and the product lyophilized to give the title compound as a TFA salt (2 mg, 56%). [M+H] calc'd for C19H25FN6, 374. found, 374.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][CH2:16][CH:17]([NH2:24])[C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:25][C:26]1[C:34]2[C:29](=[CH:30][C:31]([C:35](O)=[O:36])=[CH:32][CH:33]=2)[NH:28][CH:27]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][O:15][CH2:16][CH:17]([NH:24][C:35]([C:31]2[CH:30]=[C:29]3[C:34]([C:26]([Cl:25])=[CH:27][NH:28]3)=[CH:33][CH:32]=2)=[O:36])[C:18]2[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(COCC(N)c2ccncc2)CC1
Reactant: O=C(O)c1ccc2c(Cl)c[nH]c2c1
Product: CC(C)(C)OC(=O)N1CCC(COCC(NC(=O)c2ccc3c(Cl)c[nH]c3c2)c2ccncc2)CC1

Procedure:
Using coupling method A, 4-[2-amino-2-(4-pyridinyl)-ethoxymethyl]piperidine-1-carboxylic acid tert-butyl ester (233 mg, 0.69 mmol) and 3-chloroindole-6-carboxylic acid (149 mg, 0.76 mmol) afforded, after purification (SiO2: 10 DCM:2 EtOAc:2 Hexane:3 isopropyl amine), 118 mg (33%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[S:14]1[C:23]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18][C:17]=2[N:16]=[CH:15]1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:20]3[CH2:21][CH2:22][C:23]4[S:14][CH:15]=[N:16][C:17]=4[CH2:18][CH2:19]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Reactant: c1nc2c(s1)CCNCC2
Solvent: CN(C)C=O
Product: O=C(c1cc2ncc(Cl)cn2n1)N1CCc2ncsc2CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.19 mL (0.33 mmol, 50%) propane phosphonic acid anhydride was added to 50.0 mg (0.25 mmol) 6-chloropyrazolo[1,5-A]pyrimidine-2-carboxylic acid, 39 mg (0.25 mmol) 5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepine and 0.12 mL (0.89 mmol) TEA in 1.5 mL DMF and stirred at RT overnight. The reaction mixture was purified by chromatography and lyophilized. Yield: 17 mg (20% of theory). ESI-MS: m/z=334 (M+H)+, Rt(HPLC): 0.79 min (Method M).
Reaction SMILES: C[C:2]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N+:16]([O-])=O)=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.[CH2:19](O)C>[Pd]>[NH2:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:2][CH:3]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)[CH3:19]
Reactant: CCO
Reactant: CC(=Cc1ccccn1)c1ccccc1[N+](=O)[O-]
Agent: [Pd]
Product: CC(Cc1ccccc1N)c1ccccn1

Procedure:
2-(β-Methyl-2-nitrostyryl)pyridine (24.0 g., 0.1 mole) is hydrogenated on a Parr apparatus in 200 ml. of ethanol with 3 g. of 10% Pd/C as catalyst. The catalyst is filtered and the filtrate evaporated, providing 2-[2-(2-aminophenyl)-1-methylethyl]pyridine.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N:8]([CH2:13][C:14]([F:17])([F:16])[F:15])[C:9](=[O:12])OC)=[C:6]([NH2:18])[N:5]=[C:4]([C:19]2[C:27]3[C:22](=[N:23][CH:24]=[C:25]([F:28])[CH:26]=3)[N:21]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[F:36])[N:20]=2)[N:3]=1.Cl>O1CCCC1>[NH2:18][C:6]1[N:5]=[C:4]([C:19]2[C:27]3[C:22](=[N:23][CH:24]=[C:25]([F:28])[CH:26]=3)[N:21]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[F:36])[N:20]=2)[N:3]=[C:2]2[C:7]=1[N:8]([CH2:13][C:14]([F:16])([F:17])[F:15])[C:9](=[O:12])[NH:1]2
Reactant: COC(=O)N(CC(F)(F)F)c1c(N)nc(-c2nn(Cc3ccccc3F)c3ncc(F)cc23)nc1N
Agent: Cl
Solvent: C1CCOC1
Product: Nc1nc(-c2nn(Cc3ccccc3F)c3ncc(F)cc23)nc2[nH]c(=O)n(CC(F)(F)F)c12
Temperature: 0 °C
Reaction time: 2 h
Yield: 199.3 %

Procedure:
Under an argon atmosphere, 5.005 g (6.458 mmol) of the compound from example 32A were dissolved in 355 ml of tetrahydrofuran and cooled to 0° C., and 16.145 ml (16.145 mmol) of a 1N solution of bis(trimethylsilyl)sodium amide in tetrahydrofuran were added dropwise. The mixture was stirred at 0° C. for 2 h and then at RT for 16 h. 16.145 ml (16.145 mmol) of 1N hydrochloric acid were added and the mixture was concentrated on a rotary evaporator. The residue was taken up in ethyl acetate and the organic phase was washed twice with water, dried over sodium sulfate and concentrated on a rotary evaporator. 6.13 g of the title compound were obtained (purity by HPLC 61%). 500 mg of residue were purified by means of preparative HPLC (eluent: methanol/water, gradient 30:70→90:10). 93 mg of the title compound were obtained (36% of theory).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[S:16][C:15]3[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:14]=3[C:13]=2[CH3:22])(=[O:11])=[O:10])=[C:4]([C:23]([F:26])([F:25])[F:24])[CH:3]=1.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29](B(O)O)[CH:28]=1>COCCOC.C(O)C.C(=O)([O-])[O-].[Na+].[Na+].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>[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:2]2[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]3[S:16][C:15]4[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:14]=4[C:13]=3[CH3:22])(=[O:10])=[O:11])=[C:4]([C:23]([F:26])([F:24])[F:25])[CH:3]=2)[CH:28]=1
Reactant: Cc1c(S(=O)(=O)Nc2ccc(Br)cc2C(F)(F)F)sc2ccc(F)cc12
Reactant: OB(O)c1cccnc1
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: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: Cc1c(S(=O)(=O)Nc2ccc(-c3cccnc3)cc2C(F)(F)F)sc2ccc(F)cc12
Yield: 86.3 %

Procedure:
This compound was prepared in analogy to Example 2 starting from 5-fluoro-3-methyl-benzo[b]thiophene-2-sulfonic acid(4-bromo-2-trifluoromethyl-phenyl)-amide (0.10 g) and 3-pyridineboronic acid (0.052 g) in 1,2-dimethoxyethane (1.5 ml), ethanol (0.32 ml) and 2 M aqueous sodium carbonate solution (0.8 ml) with tetrakis(triphenylphosphine)palladium (0.050 g) to obtain the title compound (0.086 g) as a colorless solid. MS (ISP): 467.0 (M+H)+
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C@@H:15]2[CH2:20][CH2:19][CH2:18][N:17]([CH3:21])[CH2:16]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH3:21][N:17]1[CH2:18][CH2:19][CH2:20][C@@H:15]([CH2:14][N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH2:16]1
Reactant: CN1CCC[C@@H](CN2CCN(Cc3ccccc3)CC2)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CN1CCC[C@@H](CN2CCNCC2)C1
Yield: 95.2 %

Procedure:
A solution of 3.46 g of the compound obtained in step 3.3, in 100 ml of methanol, is hydrogenated in the presence of 1.9 g of wet 10% Pd/C under 800 kPa of hydrogen pressure at 40° C. for 3 hours. The medium is filtered and then evaporated, to give 2.26 g of a colourless oil.
Reaction SMILES: BrC1OC(C2N=C3C=CC(C#N)=CN3C=2)=CC=1.[C:18]([C:20]1[CH:29]=[CH:28][C:23]([C:24](=O)[CH2:25]Br)=[CH:22][CH:21]=1)#[N:19].[NH2:30][C:31]1[CH:36]=[CH:35][C:34]([Br:37])=[CH:33][N:32]=1>CCO>[Br:37][C:34]1[CH:35]=[CH:36][C:31]2[N:32]([CH:25]=[C:24]([C:23]3[CH:28]=[CH:29][C:20]([C:18]#[N:19])=[CH:21][CH:22]=3)[N:30]=2)[CH:33]=1
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Reactant: Nc1ccc(Br)cn1
Agent: N#Cc1ccc2nc(-c3ccc(Br)o3)cn2c1
Solvent: CCO
Product: N#Cc1ccc(-c2cn3cc(Br)ccc3n2)cc1
Yield: 62 %

Procedure:
The same procedure described for 3a was used employing 4-Cyanophenacyl bromide and 2-Amino-5-bromopyridine. Yield 62%, mp 218-219° C. (EtOH). 1H NMR (DMSO-d6); δ 7.41 (d, J=8.7 Hz, 1H), 7.61 (d, J=8.7 Hz, 1H), 7.90 (d, J=8.4 Hz, 2H), 8.15 (d, J=8.4 Hz, 2H), 8.53 (s, 1H), 8.92 (s, 1H). 13C NMR; δ 143.5, 143.0, 137.9, 132.7, 128.5, 127.1, 126.1, 118.8, 117.9, 111.3, 110.0, 106.4. MS (m/z, rel.int.); 298 (M+, 100). Anal. (C14H8BrN3) C, H.
Reaction SMILES: [CH2:1]([C:8]1[CH:26]=[CH:25][C:11]([C:12]([NH:14][C:15]2[CH:24]=[CH:23][C:18]([C:19](OC)=[O:20])=[CH:17][CH:16]=2)=[O:13])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].O.[NH2:28][NH2:29]>CCO>[CH2:1]([C:8]1[CH:26]=[CH:25][C:11]([C:12]([NH:14][C:15]2[CH:24]=[CH:23][C:18]([C:19]([NH:28][NH2:29])=[O:20])=[CH:17][CH:16]=2)=[O:13])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: NN
Reactant: CCCCCCCc1ccc(C(=O)Nc2ccc(C(=O)OC)cc2)cc1
Solvent: CCO
Solvent: O
Product: CCCCCCCc1ccc(C(=O)Nc2ccc(C(=O)NN)cc2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 75 %

Procedure:
To a suspension of methyl 4-[(4-heptylbenzoyl)amino]benzoate (823 mg, 2.33 mmol) in EtOH (10 mL) was added hydrazine hydrate (1.8 mL). After stirring for 15 h at reflux, the reaction mixture was cooled to rt and a white solid precipitated out. Filtration, washing with EtOH (1×2 mL) and water (2×2 mL), and drying under vacuo at rt for 72 hrs gave 619 mg of the title compound (75%) as a white solid in 99.4% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][C:8]([OH:10])=O.C(Cl)[Cl:12]>C(Cl)(=O)C(Cl)=O.CN(C)C=O>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][C:8]([Cl:12])=[O:10]
Reactant: O=C(O)CCc1cccs1
Reactant: ClCCl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)CCc1cccs1

Procedure:
To a solution of 5.0 g (0.032 mol) of 3-(2-thienyl)propionic acid in 2 ml of methylene chloride and 25 ml of oxalyl chloride was added three drops of N,N-dimethylformamide slowly. Following evolution of the gas the reaction mixture was concentrated under vacuum and 20 ml of hexane was added to the residue. The resulting mixture was filtered and the filtrate was concentrated under vacuum. The resulting compound, 3-(2-thienyl)propionyl chloride, was used directly in the following reaction.
Reaction SMILES: C(OC([NH:8][C@@H:9]([C:14]([N:16]1[CH2:36][CH2:35][CH2:34][C@H:17]1[C:18]([NH:20][CH2:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[N:29]1[CH:33]=[N:32][CH:31]=[N:30]1)=[O:19])=[O:15])[CH2:10][CH:11]1[CH2:13][CH2:12]1)=O)(C)(C)C.Cl.CCOC(C)=O>CCOC(C)=O>[CH:11]1([CH2:10][C@H:9]([C:14]([N:16]2[CH2:36][CH2:35][CH2:34][C@H:17]2[C:18]([NH:20][CH2:21][C:22]2[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=2[N:29]2[CH:33]=[N:32][CH:31]=[N:30]2)=[O:19])=[O:15])[NH2:8])[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N[C@H](CC1CC1)C(=O)N1CCC[C@H]1C(=O)NCc1cc(Cl)ccc1-n1cncn1
Agent: Cl
Solvent: CCOC(C)=O
Product: N[C@H](CC1CC1)C(=O)N1CCC[C@H]1C(=O)NCc1cc(Cl)ccc1-n1cncn1
Temperature: 0 °C

Procedure:
N-(tert-butoxycarbonyl)-3-cyclopropyl-D-alanyl-N-[5-chloro-2-(1H-1,2,4-triazol-1-yl)benzyl]-L-prolinamide from the previous step (0.058 g, 0.112 mmol) was dissolved in EtOAc (2 mL) and cooled with stirring to 0° C. HCl/EtOAc (3.55M, 1.5 mL) was added. The bath was removed and the mixture stirred for 2 hours. HPLC analysis indicated completion and the solvent was removed under reduced pressure. The residue was triturated with EtOAc and filtered to give the hydrochloride salt of 3-cyclopropyl-D-alanyl-N-[5-chloro-2-(1H-1,2,4-triazol-1-yl)benzyl]-L-prolinamide as a solid. (0.045 g). HPLC RT=1.04 min, Method B; LCMS (M+H): 417, 419; 1H NMR (400 MHz, DMSO-d6): δ 8.96, (s, 1H), 8.67 (t, J=6 Hz, 1H), 8.27–8.33 (m, 3H), 7.50–7.56 (m, 3H), 4.32 (dd, J=2, 9 Hz, 1H), 4.10–4.25 (m, 2H), 3.78–3.86 (m, 1H), 3.54–3.60 (m, 1H), 2.06–2.11 (m, 1H), 1.81–1.93 (m, 3H), 1.68–1.75 (m, 1H, 154–1.60 (m, 1H), 0.77–0.85 (m, 1H), 0.44–0.48 (m, 2H), 0.07–0.16 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:10][CH:9](OC)[N:8](C(OCC2C=CC=CC=2)=O)[C@@H:7]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:6]1)=[O:4].[H][H]>[Pd].C(O)C>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:10][CH2:9][NH:8][C@@H:7]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:6]1)=[O:4]
Reactant: COC(=O)[C@@H]1CC(OC)N(C(=O)OCc2ccccc2)[C@@H](C(=O)OC(C)(C)C)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COC(=O)[C@@H]1CCN[C@@H](C(=O)OC(C)(C)C)C1

Procedure:
A mixture of (2R,4S)-6-methoxy-piperidine-1,2,4-tricarboxylic acid 1-benzyl ester 2-tert-butyl ester 4-methyl ester (4.85 g, 11.9 mmol) and 10% palladium on carbon (500 mg) in 100 mL of ethanol was shaken under a 45 psi atmosphere of hydrogen gas for 1.5 hours. The mixture was filtered through nylon and the filtrate was concentrated to provide (2R,4R)-piperidine-2,4-dicarboxylic acid 2-tert-butyl ester 4-methyl ester as light yellow oil, which was used in the subsequent step without further purification.
Reaction SMILES: C[O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][F:12])=[N:6][C:5]=1[NH2:13].Cl>[OH-].[Na+].CO>[NH2:13][C:5]1[N:6]=[C:7]([CH2:10][CH2:11][F:12])[CH:8]=[CH:9][C:4]=1[C:3]([OH:14])=[O:2]
Reactant: COC(=O)c1ccc(CCF)nc1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1nc(CCF)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 89.9 %

Procedure:
2-Amino-6-(2-fluoro-ethyl)-nicotinic acid methyl ester (77 mg, 0.387 mmol) was dissolved in an aqueous solution of 2N sodium hydroxide (5 mL) and methanol (5 mL), and the solution was stirred for 20 minutes at room temperature. This mixture solution was neutralized with 5N hydrochloric acid, then, extracted with ethyl acetate. The organic layer was separated, the solvent was evaporated in vacuo, and the title compound (64 mg, 0.348 mmol, 90%/65% purity) was obtained as a white solid.
Reaction SMILES: C(O[C:4]([NH:6][C:7]1[CH:31]=[C:30]([S:32](=[O:35])(=[O:34])[NH2:33])[CH:29]=[CH:28][C:8]=1[C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH:20]=[C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:18][CH2:17]1)=[O:10])=[O:5])C.[OH-].[K+]>C(O)C>[C:22]1([C:19]2[CH2:18][CH2:17][N:16]([CH2:15][CH2:14][CH2:13][CH2:12][N:11]3[C:9](=[O:10])[C:8]4[C:7](=[CH:31][C:30]([S:32](=[O:34])(=[O:35])[NH2:33])=[CH:29][CH:28]=4)[NH:6][C:4]3=[O:5])[CH2:21][CH:20]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CCOC(=O)Nc1cc(S(N)(=O)=O)ccc1C(=O)NCCCCN1CC=C(c2ccccc2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: NS(=O)(=O)c1ccc2c(=O)n(CCCCN3CC=C(c4ccccc4)CC3)c(=O)[nH]c2c1

Procedure:
A mixture of 2-ethoxycarbonylamino-4-sulfamoyl-N-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]benzamide (0.16 g), potassium hydroxide (54 mg) and ethanol (10 ml) was stirred under reflux for 4 hours. After evaporation of the solvent, a small amount of water was added and the solution was neutralized with 1N hydrochloric acid. The precipitated materials were collected, triturated with ethanol and recrystallized from ethanol to give crystals of 3-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-7-sulfamoyl-1,2,3,4-tetrahydroquinazoline-2,4-dione (63
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([CH2:21][C:22]([O:24][CH2:25]C)=[O:23])[C:17]=3[CH:27]=2)[C:3]1=[O:28].[Se](=O)=[O:30]>C(O)(=O)C>[CH3:1][N:2]1[C:7]([C:8]([F:10])([F:11])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([C:21](=[O:30])[C:22]([O:24][CH3:25])=[O:23])[C:17]=3[CH:27]=2)[C:3]1=[O:28]
Reactant: O=[Se]=O
Reactant: CCOC(=O)Cc1nsc2ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12
Solvent: CC(=O)O
Product: COC(=O)C(=O)c1nsc2ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12
Reaction time: 2 h

Procedure:
A mixture of ethyl 5-[3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-1,2-benzisothiazole-3-acetate(30.0 g, 0.0750 mol), selenium dioxide (15.0 g, 0.135 mol) and glacial acetic acid is stirred two hours at reflux, cooled and filtered through a pad of Celite. The filtrate is concentrated in vacuo and the residue is stirred in methylene chloride. The mixture is filtered and the filtrate filtered through a pad of Celite. The resultant filtrate is treated with saturated sodium bicarbonate and solid sodium bicarbonate with stirring until bubbling ceases. The organic layer is saved. The aqueous layer is extracted with methylene chloride. The combined organic layers are washed with saturated sodium bicarbonate, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue is stirred overnight in diethyl ether-methylene chloride to afford, after filtration, the title compound as a white solid (24.5 g, 79.0%, mp 101-103° C.) which is identified by NMR spectral analysis.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[Cl:8].O1CCCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Si:27]([O:34][CH2:35][CH2:36]Br)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]>C(OCC)(=O)C.CCCCCC>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:36][CH2:35][O:34][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: N#CCc1ccc(Cl)c(Cl)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)[Si](C)(C)OCCC(C#N)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Combine 3,4-dichlorophenylacetonitrile (10 g, 53.8 mmol) and anhydrous tetrahydrofuran (50 mL). Cool in a dry-ice/acetone bath. Add dropwise a solution of lithium bis(trimethylsilyl)amide (64.5 mL, 1 M in THF, 64.5 mmol). Add dropwise, 2-(t-butyldimethylsilyloxy)-1-bromoethane (15.43 g, 64.5 mmol). When the addition of 2-(t-butyldimethylsilyloxy)-1-bromoethane is complete, warm the reaction mixture to ambient temperature. After 12 hours, partition the reaction mixture between ethyl acetate and water. Extract the aqueous layer twice with ethyl acetate. Combine the organic layers and extract with 1 M hydrochloric acid solution, dry over Na2SO4, filter, and concentrate in vacuo to obtain a residue. Chromatograph the residue on silica gel eluting with 10% ethyl acetate/hexane to give the title compound: Rf=0.42 (silica gel, 10% ethyl acetate/hexane).