Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]Br.[C:3]1([N:9]2[CH:13]=[CH:12][CH:11]=[N:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.O.C([O-])(O)=O.[Na+]>C(O)(=O)C.C(OCC)(=O)C>[Br:1][C:12]1[CH:11]=[N:10][N:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:13]=1
Reactant: c1ccc(-n2cccn2)cc1
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: Brc1cnn(-c2ccccc2)c1
Temperature: 100 °C
Yield: 96.8 %

Procedure:
A solution of bromine (1.1 g, 6.94 mmol) in acetic acid (10 mL) was added to a mixture of 1-phenylpyrazole (Aldrich, 1 g, 6.94 mmol) in acetic acid (10 mL). This mixture was warmed to 100° C. in a pressure tube for 8 h. The material was cooled to ambient temperature, poured into ice and H2O neutralized with excess saturated, aqueous NaHCO3. Ethyl acetate (50 mL) was added and the layers were separated. The aqueous layer was extracted with EtOAc (2×15 mL) and the combined organic extract was dried over Na2SO4 and concentrated under reduced pressure to give a crude solid. Purification by column chromatography (SiO2, 50% hexanes-EtOAc) provided the title compound (1.5 g, 6.72 mmol, 97% yield). MS (DCl/NH3) m/z 223, 225 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH2:9][N:8]([C:15]1[CH:23]=[CH:22][C:18]([C:19]([O-:21])=O)=[CH:17][N:16]=1)[CH2:7][CH2:6]2.[NH2:24][OH:25].[OH-].[Na+]>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH2:9][N:8]([C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH:24][OH:25])=[O:21])=[CH:17][N:16]=1)[CH2:7][CH2:6]2
Reactant: COc1cc2c(cc1OC)CN(c1ccc(C(=O)[O-])cn1)CC2
Reactant: NO
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1cc2c(cc1OC)CN(c1ccc(C(=O)NO)cn1)CC2
Reaction time: 72 h

Procedure:
A solution of 6-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)nicotinate (12 mg) in dioxane (0.8 mL) was treated with 50% aqueous hydroxylamine (0.2 mL). After 10 minutes the reaction was treated with 1N sodium hydroxide (0.06 mL) and the solution stirred for 72 hours. The reaction was quenched with 1N hydrochloric acid (0.06 mL) and the solvent was evaporated. The residue was purified by preparative hplc and the pure samples freeze dried to give 6-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-N-hydroxynicotinamide as a yellow solid (7.9 mg), m/e=330 (M+1). 1H NMR (DMSOd6) ppm: 2.8 (2H, m), 3.72 (6H, s) 3.9 (2H, m), 4.7 (2H, s), 6.76 (1H, s), 6.83 (1H, s), 6.9 (1H, d), 7.9 (1H, m), 8.55 (1H, s), 11 (1H, bs).
Reaction SMILES: [CH:1](/[C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([NH:18]C(=O)OCCC)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[CH:2]\[CH2:3][CH2:4][CH3:5].[OH-].[K+]>C(O)COCCO.O>[CH:1](/[C@H:6]1[CH2:7][CH2:8][C@H:9]([C:12]2[CH:13]=[CH:14][C:15]([NH2:18])=[CH:16][CH:17]=2)[CH2:10][CH2:11]1)=[CH:2]\[CH2:3][CH2:4][CH3:5]
Reactant: CCC/C=C/[C@H]1CC[C@H](c2ccc(NC(=O)OCCC)cc2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCO
Product: CCC/C=C/[C@H]1CC[C@H](c2ccc(N)cc2)CC1
Temperature: 25 °C

Procedure:
A mixture of 118 mg of propyl p-[trans-4-(trans-1-pentenyl)cyclohexyl]phenylcarbamate and 12.5 ml of a 10% solution of potassium hydroxide in diethylene glycol/water (vol. 4:1) was boiled at 120° C. for 1 hour, then cooled to room temperature and partitioned between 70 ml of diethyl ether and 70 ml of water. The aqueous phase was back-extracted twice with 70 ml of diethyl ether each time. The organic phases were washed twice with 50 ml of water each time, dried over magnesium sulphate and concentrated. Low-pressure chromatography (0.5 bar) of the brown, crystalline residue (150 mg) on 35 g of silica gel with ethyl acetate/petroleum ether (vol. 15:85) gave 76.6 mg (88%) of p-[trans-4-(trans-1-pentenyl)cyclohexyl]aniline as slightly yellowish crystals; purity 97%; Rf-value 0.24 (ethyl acetate/petroleum ether, vol. 1:5).
Reaction SMILES: C(O)=O.[ClH:4].C([N:12]1[CH2:16][C:15](=[O:17])[NH:14][CH:13]1[CH2:18][CH2:19][C:20]([O:22][CH2:23][CH:24]([CH3:26])[CH3:25])=[O:21])C1C=CC=CC=1.O>[Pd].CO>[ClH:4].[O:17]=[C:15]1[NH:14][CH:13]([CH2:18][CH2:19][C:20]([O:22][CH2:23][CH:24]([CH3:26])[CH3:25])=[O:21])[NH:12][CH2:16]1
Reactant: CC(C)COC(=O)CCC1NC(=O)CN1Cc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: O=CO
Solvent: CO
Product: CC(C)COC(=O)CCC1NCC(=O)N1
Reaction time: 6 h
Yield: 40.8 %

Procedure:
To a mixture of 10% palladium on charcoal (1 g) and 99% formic acid (1 ml) in methanol (2ml), under nitrogen, was added a solution of isobutyl 3-benzyl-5-oxo-2-imidazolidinepropanoate hydrochloride (1 g, 2.93 mmol) and 99% formic acid (1.25 ml) in methanol (25 ml). The mixture was stirred under nitrogen for 6 hours. After addition of water (15 ml) and removal of the catalyst, the solvent was evaporated and the residue was triturated with ethanol to give 0.3 g (41%) of the title compound, m.p. 136°-140° C. The same compound was obtained also by the following procedure: into a mixture of isobutyl 3-benzyl-5-oxo-2-imidazolidinepropanoate hydrochloride (2.2 g, 6.4 mmol), and 10% palladium on charcoal (1.1 g) in water-methanol 2:1 (150 ml) hydrogen was bubbled at room temperature and at atmospheric pressure for 2 hours. Removal of the catalyst and evaporation of the solvent under reduced pressure gave a residue which was triturated with ethanol to afford 1.4 g (90%) of the title compound, m.p.136°-140° C. NMR (DMSO-d6): deltaH =11.1-9.50 (b.s., 2H, NH2+); 9.20 (b.s., 1H, CONH); 4.95 (t, J=6.2 Hz, 1H, NHCHNH); 3.84 (d, J=6.7 Hz, 2H, COOCH2); 3.65 (s, 2H, NCH2CO); 2.70-2.30 (c.a., 2H, CH2CH2COO); 2.25-1.60 (c.a., 3H, CH2CH2COO, CH(CH3)2); 0.87 (d, J=6.7 Hz, 6H, CH(CH3)2. MS (E.I., 70 eV, 1.5 mA) m/z=214 (M+), 141 (M--OC4H9)+, 85 (C3H5N2O)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.Cl[C:11]1[N:29]=[C:14]2[C:15]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][CH3:28])=[CH:16][CH:17]=[CH:18][N:13]2[N:12]=1>>[CH3:28][O:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[CH2:20][NH:19][C:15]1[C:14]2[N:13]([N:12]=[C:11]([NH:1][C:2]3[CH:7]=[N:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=3)[N:29]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: COc1ccc(N)cn1
Reactant: COc1ccccc1CNc1cccn2nc(Cl)nc12
Product: COc1ccc(Nc2nc3c(NCc4ccccc4OC)cccn3n2)cn1

Procedure:
N(8)-(2-Methoxy-benzyl)-N(2)-(6-methoxy-pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-2,8-diamine was prepared from 5-amino-2-methoxypyridine (96.31 mg, 0.7758 mmol) and (2-Chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-(2-methoxy-benzyl)-amine (200.00 mg, 0.69268 mmol) in a manner analogous to Example 2d. Product isolated as a red foam (41.05 mg, 16%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.31 (s, 1H), 8.58 (s, 1H), 8.04 (d, J=9.3 Hz, 1H), 7.93 (d, J=6.8 Hz, 1H), 7.24 (m, 2H), 7.02 (d, J=8.4 Hz, 1H), 6.87 (t, J=14.9, 7.2 Hz, 1H), 6.78 (d, J=9.4 Hz, 1H), 6.72 (t, J=14.9, 7.2 Hz, 1H), 6.29 (m, 2H), 4.45 (d, J=6.0 Hz, 2H), 3.87 (s, 3H), 3.81 (s, 3H). MS=377 (MH)+.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[C:5]([O:9][C:10]([NH:12][C@@H:13]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[C:24]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:23]=1)[C:14]([O:16][C@H:17]([CH3:20])[CH2:18][OH:19])=[O:15])=[O:11])([CH3:8])([CH3:7])[CH3:6].N1C=CC=CC=1>ClCCl>[C:5]([O:9][C:10]([NH:12][C@@H:13]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[C:24]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:23]=1)[C:14]([O:16][C@H:17]([CH3:20])[CH2:18][O:19][C:1](=[O:3])[CH3:2])=[O:15])=[O:11])([CH3:6])([CH3:7])[CH3:8]
Reactant: CC(=O)Cl
Reactant: C[C@H](CO)OC(=O)[C@H](Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OC[C@@H](C)OC(=O)[C@H](Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 101 %

Procedure:
Acetyl chloride (2.3 mL, 33.1 mmol) and (1R)-2-hydroxy-1-methylethyl (2S)-2-[(tert-butoxy)carbonylamino]-3-[3,4-bis(phenylmethoxy)phenyl]propanoate (17) (11.8 g, 22.1 mmol) were dissolved in 400 mL of anhydrous dichloromethane. A solution of pyridine (2.7 mL, 33.1 mmol) in dichloromethane was added dropwise at 0° C. The mixture was stirred at room temperature for 2 hours. The product was extracted with dichloromethane, washed with 5% NaHCO3, 10% citric acid, and dried over Na2SO4. After concentration the resulting residue was further dried under vacuum. The crude product (18) (12.9 g, 100% yield) was isolated as a foamy solid. 1H NMR (400 MHz, CDCl3): δ 1.15 (d, J=6.4 Hz, 3H), 1.43 (s, 9H), 2.03 (s, 3H), 2.95 (dd, J=14.0, 6.8 Hz, 1H), 3.01 (dd, J=14.0, 6.8 Hz, 1H), 3.99 (dd, J=12.0, 6.4 Hz, 1H), 4.12 (dd, J=12.0, 3.2 Hz, 1H), 4.50 (dd, J=14.0, 6.8 Hz, 1H), 4.93 (d, 1H, NH), 5.07 (m, 1H), 5.10 (s, 4H), 6.65 (dd, J=8.0, 2 Hz, 1H), 6.76 (d, J=2.0 Hz, 1H), 6.84 (d, J=8.0 Hz, 1H), 7.28-7.46 (m, 10H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8](/[C:10](=[CH:16]/[N:17]([CH3:19])C)/[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:20])[N:3]=1.[NH2:21][CH2:22][CH2:23]C#N>C(O)C.C(OCC)C>[Cl:20][C:4]1[N:3]=[C:2]2[C:7]([C:8](=[O:9])[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:16][N:17]2[CH2:19][CH2:23][C:22]#[N:21])=[CH:6][CH:5]=1
Reactant: N#CCCN
Reactant: CCOC(=O)/C(=C\N(C)C)C(=O)c1ccc(Cl)nc1Cl
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)c1cn(CCC#N)c2nc(Cl)ccc2c1=O
Temperature: 75 °C
Reaction time: 1 h

Procedure:
A solution of EXAMPLE 81A (20 g) and 3-aminopropionitrile (4.9 mL) in 1:1 ethanol/diethyl ether (400 mL) was stirred for 15 minutes, diluted with hexanes (1 L), and filtered. The filtrant was dissolved in acetonitrile (400 mL), and the resulting solution was treated with potassium carbonate (17.4 g), heated at 75° C. for 18 hours then cooled, diluted with water (1.5 L), stirred for 1 hour, and filtered.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C@@H:4]2[CH2:5][C:6]3[C:10]([C@H:3]12)=[C:9]([CH3:11])[S:8][C:7]=3[C:12]([OH:14])=O.[CH2:16]([O:23][C:24]([NH:26][NH2:27])=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl.CCOCC>[CH2:16]([O:23][C:24]([NH:26][NH:27][C:12]([C:7]1[S:8][C:9]([CH3:11])=[C:10]2[C:6]=1[CH2:5][CH:4]1[C:2]([CH3:1])([CH3:15])[CH:3]12)=[O:14])=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NNC(=O)OCc1ccccc1
Reactant: Cc1sc(C(=O)O)c2c1[C@H]1[C@@H](C2)C1(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1sc(C(=O)NNC(=O)OCc2ccccc2)c2c1C1C(C2)C1(C)C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of (1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid (2.2 g, 9.9 mmol), hydrazinecarboxylic acid benzyl ester (3.38 g, 20.4 mmol) and DIPEA (2 mL) in DCM (50 mL) is added TBTU (3.2 g, 10 mmol). The mixture is stirred at rt for 20 h. The mixture is diluted with Et2O (200 mL) and extracted with 1 M aq. NaOH (3×50 mL) and 1 M aq. HCl (2×50 mL). The organic phase is dried (Na2SO4), filtered and evaporated to give crude N′-(1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carbonyl)-hydrazinecarboxylic acid benzyl ester; LC-MS: tR=1.01 min, [M+1]+=371.25.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:19][CH2:20][CH2:21][Cl:22]>CN(C=O)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([CH2:19][CH2:20][CH2:21][Cl:22])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCNCC1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCN(CCCCl)CC1
Yield: 69.9 %

Procedure:
Piperazine-1-carboxylic acid ethyl ester (3.0 g, 18.9 mmol), K2CO3 (2.8 g, 1.1 eq.), DMF (30 ml, 10 vol) and 1-bromo-3-chloropropane (1.8 ml, 18.9 mmol, 1 eq.) were reacted together at room temperature overnight. The reaction was quenched with water (100 ml) and extracted with DCM (3×50 ml). The combined DCM extracts were dried over MgSO4, filtered washed with DCM and concentrated in vacuo to give the title compound (3.1 g, 70%) as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:9])=[N:6][C:5]([Cl:19])=[C:4](Cl)[N:3]=1.[CH2:21]([SH:29])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].C(N(CC)CC)C>CN(C)C=O.ClCCl>[NH2:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:9])=[N:6][C:5]([Cl:19])=[C:4]([S:29][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[N:3]=1
Reactant: CCCCCCCCOC(=O)c1nc(Cl)c(Cl)nc1N
Reactant: CCCCCCCCS
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCCCCCOC(=O)c1nc(Cl)c(SCCCCCCCC)nc1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In 1 ml of dimethylformamide there was mixed n-octyl (2-amino-5,6-dichloropyrazinyl)formate (100 mg; 0.312 mol), prepared in Step B above, and n-octyl thiol (150 mg; 0.936 mol), after which there was added triethylamine (70 mg; 0.624 mol), and the reaction mixture was stirred for 1 hour at room temperature. The reaction mixture was taken up in dichloromethane and passed through a silica gel column to give the title compound. Elemental Analysis:
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=2)=[N:12][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[C:23]([C:25]1[CH:30]=[C:29]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH:28]=[CH:27][C:26]=1O)#[N:24].C1(N=C=NC2CCCCC2)CCCCC1>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([O:20][C:26]3[CH:27]=[CH:28][C:29]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[CH:30][C:25]=3[C:23]#[N:24])=[O:19])=[CH:16][CH:15]=2)=[N:12][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCCCCc1ccc(O)c(C#N)c1
Reactant: CCCCCCCc1cnc(-c2ccc(C(=O)O)cc2)nc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: CCCCCCCCCCc1ccc(OC(=O)c2ccc(-c3ncc(CCCCCCC)cn3)cc2)c(C#N)c1

Procedure:
29.8 g of 4-(5-heptylpyrimidin-2-yl)-benzoic acid (obtained from 4-(5-heptylpyrimidin-2-yl)-benzonitrile by saponification) and 25.9 g of 2-cyano-4-decylphenol are esterified with one another as described in Example 22 with addition of 21.0 g of dicyclohexylcarbodiimide. 2-Cyano-4-decylphenyl 4-(5-heptylpyrimidin-2-yl)-benzoate is obtained.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][N:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)[CH2:5][C@H:4]([CH3:18])[N:3]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].[Cl-].[NH4+]>CO.O.[Fe]>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][N:6]2[CH2:5][C@H:4]([CH3:18])[N:3]([C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[C@H:2]([CH3:1])[CH2:7]2)=[CH:10][CH:11]=1
Reactant: C[C@@H]1CN(Cc2ccc([N+](=O)[O-])cc2)C[C@H](C)N1C(=O)OC(C)(C)C
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: C[C@@H]1CN(Cc2ccc(N)cc2)C[C@H](C)N1C(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 70.4 %

Procedure:
To a solution of 1,1-dimethylethyl (2R,6S)-2,6-dimethyl-4-[(4-nitrophenyl)methyl]-1-piperazinecarboxylate (D7) (2.62 g, 7.53 mmol) in MeOH (25 mL) and water (25 mL) heated to 80° C. was added iron powder (1.26 g, 22.54 mmol) and ammonium chloride (2.01 g, 37.58 mmol). The reaction was stirred vigorously at 80° C. for 1.5 h and then the iron residues removed by filtration through Celite®. The filtrate was concentrated and the residue partitioned between DCM and water. The aqueous layer was further extracted with DCM (×2) and the combined organics were dried and concentrated to give the crude product as a yellow foam (2.01 g). Column chromatography eluting with 0-100% Et2O/petroleum ether gave the title compound (1.694 g). δH (CDCl3, 400 MHz) 7.12 (2H, d), 6.64 (2H, d), 4.05 (2H, m), 3.64 (2H, br s), 3.36 (2H, s), 2.59 (2h, d), 2.06 (2H, dd), 1.46 (9H, s), 1.27 (6H, d). MS (ES): MH+ 320.3, MNa+ 342.3.
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:21]([C:29]3[C:34]([O:35][CH3:36])=[CH:33][CH:32]=[CH:31][C:30]=3[O:37][CH3:38])=[CH:22][CH:23]=[C:24]([C:26](O)=[O:27])[CH:25]=2)=[CH:16][C:15]=1[O:39][CH2:40][CH2:41][CH2:42][N:43]([CH3:45])[CH3:44].[NH2:46][CH:47]([CH:52]([CH3:54])[CH3:53])[CH2:48][C:49]([OH:51])=[O:50]>C1COCC1.CN(C=O)C>[ClH:13].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:21]([C:29]3[C:30]([O:37][CH3:38])=[CH:31][CH:32]=[CH:33][C:34]=3[O:35][CH3:36])=[CH:22][CH:23]=[C:24]([C:26]([NH:46][CH:47]([CH:52]([CH3:54])[CH3:53])[CH2:48][C:49]([OH:51])=[O:50])=[O:27])[CH:25]=2)=[CH:16][C:15]=1[O:39][CH2:40][CH2:41][CH2:42][N:43]([CH3:44])[CH3:45]
Reactant: COc1cccc(OC)c1-c1ccc(C(=O)O)cc1-c1ccc(Cl)c(OCCCN(C)C)c1
Reactant: CC(C)C(N)CC(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1cccc(OC)c1-c1ccc(C(=O)NC(CC(=O)O)C(C)C)cc1-c1ccc(Cl)c(OCCCN(C)C)c1
Product: Cl
Temperature: 55 °C
Reaction time: 1 h

Procedure:
Add 141 mg (0.87 mmol) of CDI to a solution of 315 mg (0.67 mmol) of 4″-chloro-3″-[3-(dimethylamino)propoxy]-2,6-dimethoxy-1,1′:2′,1″-terphenyl-4′-carboxylic acid in 7 mL of anhydrous THF, and stir the reaction mixture at 55° C. for 1 h under argon. Add 70 mg (0.43 mmol) of carbonyl-1,1′-diimidazole and continue the reaction for 1 h at 50° C. Then add a suspension of 97 mg (0.74 mmol) of racemic 3-amino-4-methylpentanoic acid in a mixture of 4 mL of THF and 0.8 mL of DMF and continue stirring for 15 h at 55° C. After concentration under reduced pressure, distribute the residue obtained in 30 mL of a 2:1 DCM/water mixture. Wash the organic phase with 10 mL of water, dry over magnesium sulphate (MgSO4) and concentrate under reduced pressure. Purify the residue obtained by silica gel column chromatography, eluting with a DCM/methanol gradient from 0 to 5% of methanol. After concentration under reduced pressure, solidify the residue in ether, filter on a frit and wash with ether. We thus obtain 91 mg of 3-[({4″-chloro-3″-[3-(dimethylamino)propoxy]-2,6-dimethoxy-1,1′:2′,1″-terphenyl-4′-yl}carbonyl)amino]-4-methylpentanoic acid hydrochloride in the form of white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][CH:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[C:6]=2[CH:20]=1.[Br:21]Br>C(Cl)(Cl)(Cl)Cl>[Br:21][CH:9]1[CH:8]=[C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])[C:6]2[CH:20]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[NH:11][C:10]1=[O:12]
Reactant: BrBr
Reactant: O=C1CC=C(c2ccccc2F)c2cc(Cl)ccc2N1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1Nc2ccc(Cl)cc2C(c2ccccc2F)=CC1Br

Procedure:
A suspension of 7-chloro-5-(2-fluorophenyl)-1,3-dihydro-2H-1-benzazepin-2-one (0.378 g, 1.31 mmole) in 45 mL of dry carbon tetrachloride was heated to reflux, which generated a clear solution. Bromine (0.15 mL, 2.91 mmole) was added in two portions, 20 minutes apart, and the solution was heated at reflux for a total of 1 hour under a sunlamp. After cooling the reaction solution was washed sequentially with 5% aqueous sodium thiosulfate, dilute aqueous sodium bicarbonate, and 5% aqueous sodium thiosulfate. The organic phase was dried (sodium sulfate) and concentrated. The crude material was purified using a 2 mm chromatotron plate, eluting with 1:1 ethyl acetate-hexane, yielding 0.185 g (72%) of the title compund. IR(KBr): 3386, 1731, 1682 cm-1. Mass spec. (EI, m/z 367).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.[Br:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][NH2:22]>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([NH:22][CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[Br:18])[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: NCc1ccccc1Br
Solvent: COCCOC
Product: N#Cc1c(NCc2ccccc2Br)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile and 2-bromobenzylamine in DME. ES-MS m/e (%): 372 (M{81Br}+H+, 95), 370 (M{79Br}+H+, 100).
Reaction SMILES: [N:1]1[N:5]2[CH:6]=[CH:7][CH:8]=[N:9][C:4]2=[C:3]([C:10]([OH:12])=O)[CH:2]=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.Cl.[CH3:44][O:45][C:46]([C:48]1[CH:49]=[C:50]2[C:54](=[CH:55][CH:56]=1)[CH2:53][CH2:52][C@H:51]2[NH2:57])=[O:47]>ClCCl.C(OCC)(=O)C>[N:1]1[N:5]2[CH:6]=[CH:7][CH:8]=[N:9][C:4]2=[C:3]([C:10]([NH:57][C@H:51]2[C:50]3[C:54](=[CH:55][CH:56]=[C:48]([C:46]([O:45][CH3:44])=[O:47])[CH:49]=3)[CH2:53][CH2:52]2)=[O:12])[CH:2]=1
Reactant: COC(=O)c1ccc2c(c1)[C@H](N)CC2
Reactant: O=C(O)c1cnn2cccnc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2c(c1)[C@H](NC(=O)c1cnn3cccnc13)CC2
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.25 g, 1.533 mmol, 1 eq) was dissolved in dichloromethane (20 ml), and the mixture was cooled to 0° C. Then DIPEA (0.65 ml, 2.833 mmol, 2.5 eq), EDCI (0.34 g, 1.84 mmol, 1.2 eq) and HOBT (29 mg, 0.307 mmol, 0.2 eq) were added in succession and stirring was carried out for 15 min at RT. The reaction solution was cooled to 0° C. again, (3R)-3-amino-2,3-dihydro-1H-indene-5-carboxylic acid methyl ester hydrochloride (A-01) (0.34 g, 1.533 mmol, 1 eq), dissolved in dichloromethane (10 ml), was added, and the mixture was stirred for 16 h at RT. After monitoring by thin-layer chromatography, the reaction solution was diluted with ethyl acetate, washed in succession with 10% NH4Cl solution, sat. NaHCO3 solution and sat. NaCl solution (in each case 20 ml), dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, ethyl acetate:cyclohexane 2:1) and the desired product (R)-methyl 3-(pyrazolo[1,5-a]pyrimidine-3-carboxamido)-2,3-dihydro-1H-indene-5-carboxylate (B-07) was thus obtained. Yield: 85%
Reaction SMILES: F[C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)=O.O.[NH2:20][NH2:21]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[C:3]3[C:2](=[C:7]([CH3:8])[CH:6]=[CH:5][CH:4]=3)[NH:21][N:20]=2)=[CH:12][CH:13]=1
Reactant: NN
Reactant: COc1ccc(C(=O)c2cccc(C)c2F)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc(-c2n[nH]c3c(C)cccc23)cc1
Yield: 48.5 %

Procedure:
A solution of (2-fluoro-3-methylphenyl)-(4-methoxy-phenyl)-methanone (3.6 g, 14.7 mmol), hydrazine hydrate (4.3 mL, 140 mmol) and DMAP (1.8 g, 14.7 mmol) in pyridine was heated at 100 C for 24-48 hrs. The cooled reaction mixture was partitioned with EtOAc and 1 N HCl. The organic phase was washed with brine and dried (Na2SO4). The resulting residue was purified by flash chromatography to give the product (1.7 g) as a yellow solid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9](=[O:11])[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:12][N:13]([CH:15](OC)OC)[CH3:14]>CN(C=O)C>[CH3:12][N:13]([CH3:15])/[CH:14]=[CH:10]/[C:9](=[O:11])[CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)CCc1ccccc1
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: CN(C)/C=C/C(=O)CCc1ccccc1
Yield: 36.9 %

Procedure:
A solution of 4-phenylbutan-2-one (3.96 g, 20 mmol) and DMF-DMA (2.4 g, 20 mmol) in DMF (10 mL) was stirred at 100° C. overnight. The reaction mixture was cooled, concentrated, and purified by silica gel column (PE/EA=4:1-2:1) to give the title compound (1.5 g, 37%) as a yellow oil.