Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH2:14][CH2:13][CH2:12][C@@H:11]([C:15]([N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[O:16])[CH2:10]2)=[N:6][C:7]=1[NH2:8].[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH2:32][C@@H:31]([C:35](O)=[O:36])[CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.C(N(CC)CC)C>O1CCOCC1>[NH2:8][C:7]1[C:2]([NH:1][C:35]([CH:31]2[CH2:32][CH2:33][CH2:34][N:29]([C:27]([O:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:28])[CH2:30]2)=[O:36])=[CH:3][CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][CH2:12][C@@H:11]([C:15]([N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[O:16])[CH2:10]2)[N:6]=1
Reactant: Nc1ccc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)O)C1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCCC(C(=O)Nc2ccc(N3CCC[C@@H](C(=O)N4CCCC4)C3)nc2N)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (R)-(1-(5,6-diaminopyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone (3.60 mmol) in 1,4-dioxane (20 mL) was added (R)-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (3.60 mmol), 1-Propanephosphonic acid cyclic anhydride (10.8 mmol), and triethylamine (32.4 mmol). The reaction mixture was stirred at room temperature for 16 h. The solvent was removed under reduced pressure and a solution of methanol/dichloromethane (1:9, 50 mL) was added followed by a saturated aqueous solution of sodium bicarbonate (50 mL), and the layers were separated. The aqueous layer was extracted again with methanol/dichloromethane (1:9, 25 mL) and the combined organics were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford tert-butyl 3-((2-amino-6-((R)-3-(pyrrolidine-1-carbonyl)piperidin-1-yl)pyridin-3-yl)carbamoyl)piperidine-1-carboxylate which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1C=O.[C:15]1([NH2:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1C=CC=CC=1>[CH3:1][O:2][CH:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]1=[N:21][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COc1ccc2ccccc2c1C=O
Reactant: Nc1ccccc1
Solvent: c1ccccc1
Product: COC1C=Cc2ccccc2C1=Nc1ccccc1
Yield: 102.2 %

Procedure:
2-Methoxy-1-naphthaldehyde [50.0 gm. 0.27 mole] and phenylamine [25 gm., 0.27 mole] were refluxed with benzene [100 ml] for 4 hours. The benzene was evaporated to an oil, dissolved in chloroform, the chloroform dried over sodium sulfate and evaporated to a green semisolid of the 2-methoxy-1-naphthylidene-phenylamine [68.8 gm., 97% yield].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH3:19])[C:11]3[N:12]([C:14]([C:17]#[CH:18])=[CH:15][N:16]=3)[CH:13]=2)=[CH:4][CH:3]=1.[OH:20][CH2:21][C:22]([NH:25][S:26]([C:29]1[CH:30]=[N:31][CH:32]=[C:33](Br)[CH:34]=1)(=[O:28])=[O:27])([CH3:24])[CH3:23]>>[OH:20][CH2:21][C:22]([NH:25][S:26]([C:29]1[CH:30]=[N:31][CH:32]=[C:33]([C:18]#[C:17][C:14]2[N:12]3[CH:13]=[C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[CH:9]=[C:10]([CH3:19])[C:11]3=[N:16][CH:15]=2)[CH:34]=1)(=[O:28])=[O:27])([CH3:24])[CH3:23]
Reactant: CC(C)(CO)NS(=O)(=O)c1cncc(Br)c1
Reactant: C#Cc1cnc2c(C)cc(-c3ccc(Cl)cc3)cn12
Product: Cc1cc(-c2ccc(Cl)cc2)cn2c(C#Cc3cncc(S(=O)(=O)NC(C)(C)CO)c3)cnc12

Procedure:
The title compound was prepared from 6-(4-chloro-phenyl)-3-ethynyl-8-methyl-imidazo[1,2-a]pyridine (example C.21) (270 mg, 1 mmol) and 5-bromo-pyridine-3-sulfonic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (example B.2) (282 mg, 0.9 mmol) according to general procedure II. Obtained as a light yellow solid (180 mg, 35%). MS (ISP) 495.0 [(M+H)+], 497 [(M+2+H)+]; mp 215–217° C.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]=[CH:7][CH2:6]1)=[O:4].C=O.Cl.[OH:13][NH:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH2:22](N(CC)CC)C>C1(C)C=CC=CC=1.CCO>[C:16]1([CH2:15][N:14]2[CH2:22][C@H:7]3[CH2:6][C@H:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:9][C@H:8]3[O:13]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: ONCc1ccccc1
Reactant: COC(=O)C1CC=CC1
Reactant: CCN(CC)CC
Agent: C=O
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCO
Product: COC(=O)[C@H]1C[C@@H]2CN(Cc3ccccc3)O[C@@H]2C1
Reaction time: 24 h
Yield: 84.6 %

Procedure:
To a solution of methyl-3-cyclopentene-1-carboxylate (6.1 g, 48.4 mmole) in toluene (150 mL) and EtOH (75 mL) was added paraformaldehyde (10.6 g, 242 mmole), N-hydroxybenzylamine hydrochloride (11.4 g, 72.6 mmole) and triethylamine (10.1 mL, 72.6 mmole). After 24 hours at 80° C., the reaction solution was concentrated under vacuum and redissolved in hexanes/EtOAc, 4:1 (200 mL) and filtered. The organic solution was concentrated and then purified on silica (hexanes/EtOAc, 4:1) to give the title compound (10.7 g, 85%) as a light yellow oil containing mixture of diastereoisomers in the ratio of 6 (trans) to 1 (cis): LC-MS (ES) m/e 262 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:12][CH3:13])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:14]([O-:17])(O)=[O:15].[Na+].[CH2:19]1[CH2:23]OC[CH2:20]1>>[CH3:13][O:12][C:3]1[C:2]([NH:1][C:14]([O:17][CH2:23][CH:19]=[CH2:20])=[O:15])=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: C1CCOC1
Reactant: COC(=O)c1cccc(N)c1OC
Reactant: O=C([O-])O
Agent: [Na+]
Product: C=CCOC(=O)Nc1cccc(C(=O)OC)c1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
To a solution of methyl 3-amino-2-methoxybenzoate (94 g, 580 mmol) (from composite batches prepared as described above) in THF (1800 mL), saturated NaHCO3 (60.9 g, 725 mmol) was added. Then 2-propen-1-yl chloridocarbonate (83.7 g, 696 mmol) was added dropwise at 0° C. The mixture was stirred at rt for 2 h. The solution was extracted with EtOAc (700 mL×3). The combined organic layers were washed with water and brine successively, dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound of Step D (123 g, 80% yield), which was used in the next step directly. 1H NMR (400 MHz, CDCl3) δ ppm 8.25-8.35 (m, 1H), 7.49-7.53 (m, 1H), 7.36-7.42 (br, 1H), 7.10-7.18 (m, 1H), 5.91-6.07 (m, 1H), 5.75-5.90 (m, 2H), 4.63-4.70 (m, 2H), 3.92 (s, 3H), 3.86 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH3:15].[CH3:16][O:17][C:18](=[O:46])[CH2:19][CH2:20][C:21]1[CH:26]=[C:25]([O:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])[CH:24]=[CH:23][C:22]=1[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]OS(C)(=O)=O>>[CH3:16][O:17][C:18](=[O:46])[CH2:19][CH2:20][C:21]1[CH:26]=[C:25]([O:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])[CH:24]=[CH:23][C:22]=1[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][O:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH3:15]
Reactant: CCCc1c(O)ccc2c1OCCC2=O
Reactant: COC(=O)CCCOc1ccc(CCCCCCOS(C)(=O)=O)c(CCC(=O)OC)c1
Product: CCCc1c(OCCCCCCc2ccc(OCCCC(=O)OC)cc2CCC(=O)OC)ccc2c1OCCC2=O
Yield: 86.7 %

Procedure:
Using the procedure of example 11 and starting with 0.28 g (1.4 mmol) of 2,3-dihydro-7-hydroxy-8-propyl-4H-1-benzopyran-4-one and 0.64 g (1.4 mmol) of 2-[6-[(methylsulfonyl)oxy]hexyl]-5-(4-methoxy-4-oxobutoxy)benzenepropanoic acid methyl ester (from example 53), 5-(4-methoxy-4-oxobutoxy)-2-[6-[(3,4-dihydro-4-oxo-8-propyl-2H-1-benzopyran-7-yl)oxy]hexyl]benzenepropanoic acid methyl ester was obtained in 86.7% yield (0.69g) as an oil. This diester (1.21 mmol) was saponified with 2 mL of 3N aqueous lithium hydroxide in 20 mL of tetrahydrofuran, at room temperature, for 24 hr. Work-up as in example 4 gave a light-brown oily acid which was flash-chromatographed on silica gel, eluting with 95:5:1 chloroform-methanol-acetic acid. There was obtained 0.6 g (91.8%) of pure 5-(3-carboxypropoxy)-2-[6-[(3,4-dihydro-4-oxo-8-propyl-2H-1-benzopyran-7-yl)oxy]hexyl]benzenepropanoic acid. Recrystallization from hexane-ethyl acetate gave 0.49 g (75%) of a colorless solid, mp 119°-120° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][O:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=1.[N-:18]=[N+:19]=[N-:20].[Na+].C(O)(=O)C>C(O)CCC>[Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][O:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]2[NH:20][N:19]=[N:18][N:12]=2)=[CH:9][CH:8]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc(OCc2cccc(Cl)c2)cc1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCCCO
Product: Clc1cccc(COc2ccc(-c3nnn[nH]3)cc2)c1

Procedure:
To a solution of 5×10-2 mole of 4-(3-chloro benzyloxy) benzonitrile in 20 ml of butanol are added 6.6×10-2 mole of sodium azide and 6.6×10-2 of acetic acid. Then the reaction mixture is heated to reflux for four days. 1 g of sodium azide, 2 g of acetic acid and 10 ml of butanol are added and the medium is again heated for two days at reflux. After concentrating by evaporating the solvent, the residue is taken up in 20 ml of 10% aqueous NaOH. After filtration, the aqueous phase is extracted with ether. By acidification of the alkaline solution using HCl 2N, the expected compound precipitates and is recrystallized in methanol.
Reaction SMILES: [CH3:1][CH2:2][N:3]([CH:7]([CH3:9])C)[CH:4]([CH3:6])[CH3:5].ClC(OCC1C=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=1)=O.CN(C)C=[O:27]>>[CH3:9][CH2:7][N:3]([C:4]1[CH:5]=[CH:19][C:18]([NH2:21])=[C:17]([CH3:16])[CH:6]=1)[CH2:2][CH2:1][OH:27]
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Reactant: CN(C)C=O
Reactant: CCN(C(C)C)C(C)C
Product: CCN(CCO)c1ccc(N)c(C)c1
Reaction time: 72 h

Procedure:
To 50 mg of Rho575 in dimethylformamide, 53 μl of N,N′-diisopropylethylamine was added followed by 78 mg of p-nitrobenzyl chloroformate dissolved in dimethylformamide. The reaction mixture was stirred for 3 days and the solvent was removed in vacuo. The residue was dissolved in chloroform and purified on a Biotage SP4 System with a SNAP 25 g column and a chloroform methanol gradient, to give a pink product.
Reaction SMILES: C([O:8][C:9]([C:11]1([N:16]([CH:34]=[CH:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[S:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:10])C1C=CC=CC=1.[H][H]>C(O)C.O>[CH2:39]([O:38][C:36]([CH2:35][CH2:34][N:16]([S:17]([C:20]1[CH:21]=[CH:22][C:23]([O:26][C:27]2[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=2)=[CH:24][CH:25]=1)(=[O:19])=[O:18])[C:11]1([C:9]([OH:10])=[O:8])[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:37])[CH3:40]
Reactant: [H][H]
Reactant: CCOC(=O)C=CN(C1(C(=O)OCc2ccccc2)CCCC1)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Solvent: CCO
Solvent: O
Product: CCOC(=O)CCN(C1(C(=O)O)CCCC1)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1

Procedure:
A solution of 2.50 g (4.4 mmol) of 1-{(2-ethoxycarbonylvinyl)-[4-(4-fluorophenoxy)benzenesulfonyl]amino}cyclopentanecarboxylic acid benzyl ester in 25 mL of ethanol was treated with 2.5 9 of 50% water wet 10% palladium on carbon catalyst and shaken under 53 psi of hydrogen for 21 hours. The catalyst was removed by filtration and washed with ethanol (4×25 mL). The filtrate and washings were combined and concentrated under vacuum to 1.74 g (82%) of crude 1-{(2-ethoxycarbonylethyl)-[4-(4-fluorophenoxy)benzenesulfonyl]amino}cyclopentanecarboxylic acid_ as a viscous oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[C:4]([F:17])[CH:3]=1.C([Li])CCC.C([O:26][B:27](OC(C)C)[O:28]C(C)C)(C)C>>[F:17][C:4]1[CH:3]=[C:2]([B:27]([OH:28])[OH:26])[CH:7]=[CH:6][C:5]=1[O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CCCCCCCCOc1ccc(Br)cc1F
Agent: [Li]CCCC
Product: CCCCCCCCOc1ccc(B(O)O)cc1F

Procedure:
This was prepared using a similar method to that described for compound 5. Quantities: 1-bromo-3-fluoro-4-octoxybenzene (15 g, 0.05 mol), n-butyllithium (5 ml, 10M in hexane, 0.05 mol), tri-isopropylborate (18.81 g, 0.1 mol).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:9]1[C:10]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[C:11]2[C:16](=[CH:17][C:18]=1[CH3:19])[NH:15][C:14](=[O:20])[CH:13]=[CH:12]2)[CH2:7][OH:8])([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[Si:33](Cl)([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34]>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C@@H:6]([C:9]1[C:10]([C:21]2[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=2)=[C:11]2[C:16](=[CH:17][C:18]=1[CH3:19])[NH:15][C:14](=[O:20])[CH:13]=[CH:12]2)[CH2:7][O:8][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc2[nH]c(=O)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](CO)OC(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc2[nH]c(=O)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](CO[Si](C)(C)C(C)(C)C)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.6 %

Procedure:
To a solution of (S)-6-(1-tert-butoxy-2-hydroxyethyl)-5-(4-chlorophenyl)-7-methylquinolin-2(1H)-one (8K) (0.5175 g, 1.34 mmol) in DMF (5.0 mL), was added imidazole (0.204 g, 4.02 mmol), followed by tert-butyldimethylsilyl chloride (0.243 g, 1.61 mmol) at 0° C. The reaction mixture was warmed to room temperature overnight. Additional imidazole (0.2 g) and tert-butyldimethylsilyl chloride (0.30 g) were added and the mixture stirred for another 2 hours. The reaction mixture was the diluted with ethyl acetate, washed with 5% lithium chloride solution (2×), brine, dried (MgSO4), filtered, concentrated and purified by flash column chromatography (silica gel, 20 to 60% ethyl acetate/hexanes) to give a yellow foam (0.500 g). LCMS-ESI+ (m/z): calcd for C28H39ClNO3Si: 501.1;
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[N:14]=[C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][N:16]2[CH:22]=1.[CH:23]1([CH2:26][C:27](O)=[O:28])[CH2:25][CH2:24]1.C(N(CC)C(C)C)(C)C.[Cl-].[Na+].O.O>CN(C=O)C>[CH:23]1([CH2:26][C:27]([NH:21][C:18]2[CH:19]=[CH:20][C:15]3[N:16]([CH:22]=[C:13]([C:3]4[C:4]([C:7]5[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=5)=[N:5][O:6][C:2]=4[CH3:1])[N:14]=3)[CH:17]=2)=[O:28])[CH2:25][CH2:24]1
Reactant: O=C(O)CC1CC1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn2cc(N)ccc2n1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cc1onc(-c2ccccc2)c1-c1cn2cc(NC(=O)CC3CC3)ccc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.7 %

Procedure:
A solution of 2-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazo[1,2-a]pyridin-6-ylamine (63.9 mg, 0.22 mmol) in DMF (0.2 mL) was added to a solution containing of cyclopropylacetic acid (20 μL, 0.22 mmol), N,N,N′,N′-tetramethyl-O-(benzotriazol-1-yl)uranium tetrafluoroborate (70.6 mg, 0.22 mmol), N,N-diisopropyl ethyl amine (129 μL, 1.0 mmol) in DMF (0.3 mL) and the resulting mixture stirred at room temperature for 2 h. The resulting mixture was then poured into a mixture of brine:water (1:1) and extracted with ethyl acetate. The combined organic layers were then washed with brine, dried over sodium sulphate and evaporated to leave a brown solid. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 50:50) afforded the title compound (44 mg, 59%) which was obtained as a light green solid. MS: m/e=373.3 [M+H]+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]#[C:9][CH2:10][C:11]#[C:12][CH2:13][C:14]#[C:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].N1C=CC=CC=1.[H][H]>[Pd].O>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCC#CCC#CCC#CCCCCCCCl
Reactant: [H][H]
Agent: [Pd]
Solvent: c1ccncc1
Solvent: O
Product: CCCCC/C=C\C/C=C\C/C=C\CCCCCCCl

Procedure:
A mixture of 35.9 g. of 1-chloro-7,10,13-nonadecatriyne dissolved in 200 ml. of pyridine and 5.4 g. of 5% palladium on barium sulfate was shaken in an atmosphere of hydrogen in a Parr hydrogenator for 1.25 hrs. (pressure drop 21.5 lb.; 0.1 mole hydrogen = 8.5 lb.), then the reaction mixture was poured into water and extracted with ether. The ether extract was washed several times with water, then with dilute hydrochloric acid, followed by saturated aqueous sodium chloride. The ether solution was then dried over sodium sulfate, and evaporated under reduced pressure leaving a residue comprising 1-chloro-cis,cis,cis-7,10,13-nonadecatriene which was further purified by distillation on a shaking short path distillation apparatus, giving 27 g. of 1-chloro-cis,cis,cis-7,10,13--nonadecatriene collected at a jacket temperature of 180°-190°/0.005 mm.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH2:9][OH:10])[CH:6]=[CH:5][C:4]=1[OH:11])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].CCOC(C)=O>C(#N)C.O>[CH2:1]([C:3]1[CH:8]=[C:7]([CH2:9][OH:10])[CH:6]=[CH:5][C:4]=1[O:11][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH3:2]
Reactant: CCc1cc(CO)ccc1O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1ccc(CO)cc1CC
Reaction time: 18 h
Yield: 61.6 %

Procedure:
To a solution of 2-ethyl-4-(hydroxymethyl)phenol (3.67 g, 24.1 mmol) in anhydrous acetonitrile (125 mL) was added caesium carbonate (8.65 g, 26.6 mmol), the reaction mixture was then flushed with nitrogen and cooled to 0° C. before addition of ethyl bromoacetate (2.68 mL, 24.1 mmol). The reaction mixture was allowed to gradually attain room temperature and stirred for 18 h. Further ethylbromoacetate (0.26 mL, 2.4 mmol) was added and stirring continued for 4 h. The reaction mixture was diluted with water (100 mL) and then extracted EtOAc (2×100 mL). The combined organic extracts were dried (MgSO4) filtered and evaporated. Purification by Biotage™ chromatography (Silica, 90 g) eluting 4:1 cyclohexane:EtOAc, then EtOAc afforded the title compound as a pale yellow gum (3.54 g).
Reaction SMILES: [N-]1C=CN=C1.[CH3:6][C:7]1[NH:8][C:9]([CH3:26])=[C:10]([C:23]([OH:25])=O)[CH:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])[C:12]=1[N+:13]([O-:15])=[O:14].[SH:27]C(O)C.[O:31]1CC[CH2:33][CH2:32]1>>[CH3:6][C:7]1[NH:8][C:9]([CH3:26])=[C:10]([C:23](=[S:27])[O:25][CH2:33][CH2:32][OH:31])[CH:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])[C:12]=1[N+:13]([O-:15])=[O:14]
Reactant: CC(O)S
Reactant: C1CCOC1
Reactant: CC1=C(C(=O)O)C(c2ccccc2Cl)C([N+](=O)[O-])=C(C)N1
Agent: c1c[n-]cn1
Product: CC1=C(C(=S)OCCO)C(c2ccccc2Cl)C([N+](=O)[O-])=C(C)N1

Procedure:
3 g of 1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-chlorophenyl)-pyridine-5-carboxylic acid imidazolide are boiled in 12.5 ml of absolute tetrahydrofuran with 5 ml of mercaptoethanol for 7 hours. The mixture is concentrated, the concentrate is concentrated at 70° C. using an oil pump, the residue is dissolved in chloroform and the solution is washed twice with water, dried and concentrated. The resulting evaporation residue is purified over a silica gel column with a volume of 160 ml, using toluene and later toluene/ethyl acetate 6:1 as the mobile phase. 1.94 g of a yellow foam with an Rf value of 0.25 are obtained as the main fraction.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([C:13]3[C:14]4[C:19]([C:20]([C:27]5[C:36]6[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=6)[CH:30]=[CH:29][CH:28]=5)=[C:21]5[C:26]=3[CH:25]=[CH:24][CH:23]=[CH:22]5)=[CH:18][CH:17]=[CH:16][CH:15]=4)=[CH:10]2)=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1.CN1CCCC1=O>O>[C:27]1([C:20]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([C:9]3[CH:10]=[C:11]4[C:6]([CH:5]=[CH:4][C:3]([OH:2])=[CH:12]4)=[CH:7][CH:8]=3)=[C:26]3[C:21]=2[CH:22]=[CH:23][CH:24]=[CH:25]3)[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: COc1ccc2ccc(-c3c4ccccc4c(-c4cccc5ccccc45)c4ccccc34)cc2c1
Agent: Cl
Solvent: O
Solvent: CN1CCCC1=O
Solvent: c1ccncc1
Product: Oc1ccc2ccc(-c3c4ccccc4c(-c4cccc5ccccc45)c4ccccc34)cc2c1
Temperature: 200 °C
Reaction time: 6.5 h

Procedure:
Under the nitrogen atmosphere, 9-(7-methoxynaphthalen-2-yl)-10-(naphthalen-1-yl)anthracene (17.5) as the third intermediate compound, pyridine hydrochloride (22.0 g) and N-methylpyrrolidone (35 ml) were added to a flask and stirred for 6.5 hours at 200° C. Once the heating is completed, the reaction solution was cooled to 100° C. or less, added with water, and the precipitated solid was collected by suction filtration. The crude product obtained was purified by silica gel column chromatography (solvent: toluene) to give 7-(10-(naphthalen-1-yl)anthracen-9-yl)naphthalene-2-ol (16.0 g) as a fourth intermediate compound. The scheme is shown in the following “Reaction 5”.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C:20](O)=[O:21])[C:7]3[C:12]([CH3:13])=[N:11][N:10]([CH:14]4[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]4)[C:8]=3[N:9]=2)[CH2:3][CH2:2]1.[NH2:23][CH2:24][C:25]1[C:26](=[O:33])[NH:27][C:28]([CH3:32])=[CH:29][C:30]=1[CH3:31]>>[CH:14]1([N:10]2[C:8]3[N:9]=[C:4]([CH:1]4[CH2:2][CH2:3]4)[CH:5]=[C:6]([C:20]([NH:23][CH2:24][C:25]4[C:26](=[O:33])[NH:27][C:28]([CH3:32])=[CH:29][C:30]=4[CH3:31])=[O:21])[C:7]=3[C:12]([CH3:13])=[N:11]2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Reactant: Cc1nn(C2CCCCC2)c2nc(C3CC3)cc(C(=O)O)c12
Product: Cc1cc(C)c(CNC(=O)c2cc(C3CC3)nc3c2c(C)nn3C2CCCCC2)c(=O)[nH]1

Procedure:
The title compound was prepared in the same manner as described in example 109 using 6-cyclopropyl-1-(1-cyclohexyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (150 mg, 0.501 mmol), and 3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone (123 mg, 0.651 mmol). The product was collected as a solid, 0.190 g (87%). LCMS E-S (M+H)=434.2. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.95-1.07 (m, 4H), 1.15-1.31 (m, 1H), 1.36-1.52 (m, 2H), 1.68 (br. s., 1H), 1.77-1.99 (m, 6H), 2.11 (s, 3H), 2.18-2.29 (m, 4H), 2.35 (s, 3H), 4.33 (d, J=4.80 Hz, 2H), 4.53-4.73 (m, 1H), 5.87 (s, 1H), 6.96 (s, 1H), 8.58 (t, J=4.93 Hz, 1H), 11.51 (s, 1H).
Reaction SMILES: [Cl:1][C:2]([Cl:7])([Cl:6])[C:3](Cl)=[O:4].[CH3:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:21]=[CH:20][C:19]([C:22]([N:24]2[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[CH2:28][N:27]3[CH:35]=[CH:36][CH:37]=[C:26]3[CH2:25]2)=[O:23])=[CH:18][CH:17]=1.C(N(CC)C(C)C)(C)C>ClCCl>[Cl:1][C:2]([Cl:7])([Cl:6])[C:3]([C:35]1[N:27]2[C:26]([CH2:25][N:24]([C:22]([C:19]3[CH:20]=[CH:21][C:16]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[O:9][CH3:8])=[CH:17][CH:18]=3)=[O:23])[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[CH2:28]2)=[CH:37][CH:36]=1)=[O:4]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: COc1ccccc1-c1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
Trichloroacetyl chloride (2.63 mL, 23.6 mmol) was added dropwise over five minutes to a solution of (2′-methoxy-biphenyl-4-yl)-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone (3.0 g, 7.60 mmol) and N,N-diisopropylethyl amine (2.65 mL, 15.2 mmol) in dichloromethane (60 mL). The reaction was stirred under nitrogen at room temperature overnight and then quenched with water. The organic layer was washed with 0.1N hydrochloric acid and water, dried over anhydrous magnesium sulfate, filtered and concentrated to an oil. The oil was purified by flash chromatography over silica gel Merck-60 using a 0-5% gradient of ethyl acetate in dichloromethane to give the title compound (2.34 g) as a yellow foam.