Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]([N:24]1[CH2:29][CH2:28][CH:27]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=2)[CH2:26][CH2:25]1)[CH2:3][NH:4][C:5]([C:7]1[N:8]=[N:9][N:10]([CH:12]2[CH2:16][CH2:15][N:14](CC3C=CC=CC=3)[CH2:13]2)[CH:11]=1)=[O:6].C(N1CCC(N)C1)C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[O:1]=[C:2]([N:24]1[CH2:29][CH2:28][CH:27]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:38])([F:39])[F:40])[CH:32]=2)[CH2:26][CH2:25]1)[CH2:3][NH:4][C:5]([C:7]1[N:8]=[N:9][N:10]([CH:12]2[CH2:16][CH2:15][NH:14][CH2:13]2)[CH:11]=1)=[O:6]
Reactant: O=C(NCC(=O)N1CCC(Oc2cccc(C(F)(F)F)c2)CC1)c1cn(C2CCN(Cc3ccccc3)C2)nn1
Agent: [Pd+2]
Agent: NC1CCN(Cc2ccccc2)C1
Agent: [OH-]
Solvent: CO
Product: O=C(NCC(=O)N1CCC(Oc2cccc(C(F)(F)F)c2)CC1)c1cn(C2CCNC2)nn1
Reaction time: 6 h
Yield: 80.2 %

Procedure:
Pd(OH)2 (80 mg) was added to a stirred solution of 1-(1-benzyl-pyrrolidin-3-yl)-1H-[1,2,3]triazole-4-carboxylic acid {2-oxo-2-[4-(3-trifluoromethyl-phenoxy)-piperidin-1-yl]-ethyl}-amide (prepared by the method used for the synthesis of Example 136, starting from 1-benzyl-3-aminopyrrolidine) (407 mg, 0.73 mmol) in MeOH (4 mL) in an inert atmosphere and stirring was continued under H2 gas atmosphere for 6 hrs. The reaction mixture was filtered through celite. The filtrate collected was concentrated under reduced pressure to afford 260 mg (80.2% Yield) of 1-pyrrolidin-3-yl-1H-[1,2,3]triazole-4-carboxylic acid {2-oxo-2-[4-(3-trifluoromethyl-phenoxy)-piperidin-1-yl]-ethyl}-amide. LC/MS [M+H]+: 467.19.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[C:9]([F:14])([F:13])[CH2:8][N:7]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:20]=1.[NH2:21][C:22]1[CH:36]=[CH:35][C:25]([C:26]([NH:28][CH:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[O:27])=[CH:24][CH:23]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)C>[CH:15]1([N:7]2[CH2:8][C:9]([F:14])([F:13])[C:10](=[O:12])[NH:11][C:5]3[CH:4]=[N:3][C:2]([NH:21][C:22]4[CH:23]=[CH:24][C:25]([C:26]([NH:28][CH:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)=[O:27])=[CH:35][CH:36]=4)=[N:20][C:6]2=3)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=C1Nc2cnc(Cl)nc2N(C2CCCC2)CC1(F)F
Reactant: Nc1ccc(C(=O)NC2CCOCC2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Solvent: O
Product: O=C(NC1CCOCC1)c1ccc(Nc2ncc3c(n2)N(C2CCCC2)CC(F)(F)C(=O)N3)cc1
Yield: 84.6 %

Procedure:
A mixture of 0.05 g (0.17 mmole) of 2-chloro-9-cyclopentyl-7,7-difluoro-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-20), 0.04 g (0.20 mmole) of 4-amino-N-(tetrahydro-pyran-4-yl)-benzamide and 0.05 g (0.25 mmole) of p-toluenesulfonic acid monohydrate in 4.0 mL of 2-propanol was heated at 160 degrees for 2 hours in a microwave reactor. The cooled mixture was then concentrated under reduced pressure. The residue was diluted with dichloromethane and washed twice with saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted with dichloromethane, and the combined organic layers washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was washed with water and dried to give 0.070 g of 4-(9-cyclopentyl-7,7-difluoro-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(tetrahydro-pyran-4-yl)-benzamide (I-136).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20](=[O:23])[NH:21][CH3:22])[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:24]([O:26]CC)=[O:25])=[CH:5][CH:4]=1.[Li+].[OH-]>CO.C1COCC1.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20](=[O:23])[NH:21][CH3:22])[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:24]([OH:26])=[O:25])=[CH:5][CH:4]=1
Reactant: CCOC(=O)c1cnc2ccc(C(=O)NC)cc2c1Nc1ccc(OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CNC(=O)c1ccc2ncc(C(=O)O)c(Nc3ccc(OC)cc3)c2c1
Yield: 76.7 %

Procedure:
Ethyl 4-[(4-methoxyphenyl)amino]-6-(methylcarbamoyl)quinoline-3-carboxylate (0.2 g) was stirred with LiOH (85.5 mg) in 6 mL of MeOH:THF:H2O (2:2:2) overnight. The reaction mixture was concentrated and the aqueous layer was washed with ethyl acetate. The aqueous layers were collected and acidified with aqueous HCl and the precipitate formed was filtered and dried to give 0.142 g (60%) of 4-[(4-methoxyphenyl)amino]-6-(methylcarbamoyl)-quinoline-3-carboxylic acid. 1H NMR (300 MHz, CD3OD) δ 9.05 (s, 1H, aromatic), 8.20 (s, 1H, aromatic), 8.12-7.81 (m, 2H, aromatic), 7.27 (d, 2H, J=9.9 Hz, aromatic), 7.06 (d, 2H, J=9.9 Hz, aromatic), 3.88 (s, 1H, —OCH3), 2.82 (s, 3H, —NCH3); LC-MS (m/z) 352.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:11]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=O)=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.Cl.[NH2:20][OH:21].C(N(CC)C(C)C)(C)C.CC(O)=O>C(O)CCC>[Cl:1][C:2]1[C:3]([C:11]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[N:20][OH:21])=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: NO
Reactant: O=C(c1c(Cl)cnc2[nH]ccc12)C1CCCCC1
Agent: Cl
Solvent: CC(=O)O
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: ON=C(c1c(Cl)cnc2[nH]ccc12)C1CCCCC1
Temperature: 120 °C

Procedure:
A mixture of (5-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)(cyclohexyl)methanone (0.35 g, 1.33 mmol; Example #23, Step B), hydroxylamine hydrochloride (0.46 g, 6.7 mmol), N,N-diisopropylethylamine (1.6 mL, 9.32 mmol) and AcOH (0.2 mL, 3.5 mmol) in n-butanol (20 mL) was heated at about 120° C. for about 18 h. Additional hydroxylamine hydrochloride (0.185 g, 2.66 mmol), N,N-diisopropylethylamine (0.70 mL, 4.0 mmol), and AcOH (0.15 mL, 2.7 mmol) were added to the mixture and the reaction was heated at about 120° C. for about 18 h. Additional amounts of hydroxylamine hydrochloride (0.185 g, 2.66 mmol), DIEA (0.70 mL, 4.0 mmol), and AcOH (0.15 mL, 2.7 mmol) were added to the mixture and the reaction was heated at about 130° C. for about 3 days. The reaction was cooled to ambient temperature and concentrated under reduced pressure. The residue was diluted with EtOAc (50 mL) and washed with saturated aqueous NaHCO3 (3×40 mL) and brine (20 mL), dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (0-70% EtOAc in heptane gradient as the eluent to provide (5-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)(cyclohexyl)methanone oxime as an off white solid (0.193 g, 52%): LC/MS (Table 2, Method a) Rt=2.22 min; m/z: 276 and 278 (M−H)−.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[C:11]([NH:18][C@H:19]([CH2:27][OH:28])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].C(N(CC)CC)C>C(Cl)Cl>[C:11]([NH:18][C@H:19]([CH:27]=[O:28])[CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)([O:13][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:12]
Reactant: CC(C)(C)OC(=O)N[C@H](CO)Cc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](C=O)Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 85.1 %

Procedure:
To dimethyl sulfoxide (2.82 mL, 39.8 mmol) dissolved in anhydrous methylene chloride (5 mL) and cooled to -78° C. was added dropwise oxalyl chloride (2.6 mL, 1.5 equiv). After 10 minutes at -78° C. N-Boc-Phenylalaninol (5.00 g, 19.9 mmol) dissolved in anhydrous methylene chloride (75 mL) was cannulated into the reaction mixture. After 15 minutes at -78° C., the reaction was stirred for 2 minutes at 0° C. and then cooled again to -78° C. Triethylamine (11.9 mL, 4.3 equiv) was added dropwise. After 25 minutes, the reaction was quenched with cooled 10% citric acid (15 mL) and then diluted with additional 10% citric acid (75 mL). Ether (300 mL) was added and the solution was washed with water (5×100 mL), brine, water (5×100 mL), and brine, dried over sodium sulfate, and concentrated under reduced pressure to afford the title compound (4.22 g).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]2[CH2:13][CH:12]2[C:14](OCC)=[O:15])=[N:3]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1.O>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]2[CH2:13][CH:12]2[CH2:14][OH:15])=[N:3]1
Reactant: CCOC(=O)C1CC1c1nn(C)c2ccccc12
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: Cn1nc(C2CC2CO)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of ethyl 2-(1-methyl-1H-indazol-3-yl)cyclopropanecarboxylate (1.17 g, 5 mmol) in THF (20 mL) was cooled to 0° C. and treated slowly with LAH (270 mg, 7 mmol). The solution was warmed to room temperature and stirred overnight. The reaction mixture was then re-cooled to 0° C. and treated sequentially with 0.3 mL of water, 0.3 mL of 15% NaOH, and 0.9 mL of water. Sodium sulfate was added to the mixture. After stirring at room temperature for 10 min, the mixture was filtered through a pad of Celite and the filtrate was concentrated in vacuo to afford the title compound as pale yellow oil. LRMS m/z (M+H) 204.1 found, 204.1 required. Enantiomers can be resolved by chiral analytical SFC ((R,R)-Whelk-O14.6*250 mm 5 um) ent1=4.37 min (1S,2S) (active isomer, 360 mg), ent2=5.33 min.
Reaction SMILES: [H-].[Na+].[NH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[CH3:15][CH2:16][CH2:17]I.O>CS(C)=O>[NH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[CH2:15][CH2:16][CH3:17]
Reactant: CCCI
Reactant: NCCCCNc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCCN(CCCCN)c1ccccn1
Yield: 66.9 %

Procedure:
Sodium hydride (1.1 g) was dissolved in DMSO (20 ml) at 70°-75° C. under nitrogen. The solution was cooled and a solution of 2-(4-aminobutylamino)pyridine (6.9 g) in DMSO (20 ml) added at room temperature. N-Propyl iodide (7.81 g) in DMSO (10 ml) was added dropwise maintaining the temperature at 25°-35° C. After a further 15 min. water (200 ml) was added and the mixture was extracted with ether. The ether extract was washed with hydrochloric acid (2N) and the aqueous layer made alkaline to pH 6. After extracting with chloroform, the pH of the aqueous layer was raised to pH 14 and extracted with ether. The ether extracts were washed with 0.1N sodium hydroxide, dried (K2CO3) and the ether evaporated to give 2-[N-(4-aminobutyl)-N-propylamino]pyridine (5.79 g) as an oil which was used without further purification.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[C:13]1[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[CH:14]=1.B(Br)(Br)Br>ClCCl>[NH2:19][C:15]1[CH:14]=[C:13]([C:4]2[CH:5]=[C:6]([C:9]([F:11])([F:10])[F:12])[CH:7]=[CH:8][C:3]=2[OH:2])[CH:18]=[CH:17][N:16]=1
Reactant: COc1ccc(C(F)(F)F)cc1-c1ccnc(N)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Nc1cc(-c2cc(C(F)(F)F)ccc2O)ccn1
Temperature: 25 °C
Reaction time: 20 h
Yield: 52319.4 %

Procedure:
To 4-[2-methoxy-5-(trifluoromethyl)phenyl]pyridin-2-amine (Preparation 16, 2.8 g, 0.01 mmol) in dichloromethane (5 mL) at 0° C. was added drop-wise a 1.0 M solution of boron tribromide in dichloromethane (31.3 mL, 31.3 mmol). After stirring for 20 hours at ambient temperature, the reaction mixture was quenched with water and saturated aqueous sodium bicarbonate until basic. The aqueous phase was extracted with 15% isopropyl alcohol in chloroform (×3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (0% to 10% methanol in chloroform gradient elution) and concentrated in vacuo to afford the title compound as a yellow solid (1.33 g).
Reaction SMILES: [SH:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6].[H-].[Na+].C(OCCO)C.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19](Br)[N:18]=1>>[NH2:16][C:17]1[N:18]=[C:19]([S:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6])[CH:20]=[CH:21][CH:22]=1
Reactant: Nc1cccc(Br)n1
Reactant: O=C(O)CCCS
Agent: [H-]
Agent: [Na+]
Solvent: CCOCCO
Product: Nc1cccc(SCCCC(=O)O)n1
Yield: 62.9 %

Procedure:
A mixture of 4-mercaptobutyric acid (0.72 g.) a 50% w/w dispersion of sodium hydride in mineral oil (0.58 g.) and 2-ethoxyethanol (5 ml.) was treated with 2-amino-6-bromopyridine (0.35 g.) and the mixture was heated under reflux for 18 hours and then evaporated to dryness. The residue was partitioned between water and EtOAc and the aqueous phase was neutralised with HOAc. The precipitated yellow solid was collected to give 4-(6-aminopyrid-2-ylthio)butyric acid (0.27 g.) which was used without further purification.
Reaction SMILES: [F:1][CH2:2][C:3]1([CH2:20][F:21])[CH:8]=[C:7]([C:9](O)=[O:10])[C:6]2[CH:12]=[C:13]([C:16]([F:19])([F:18])[F:17])[CH:14]=[CH:15][C:5]=2[O:4]1.[C:22]([CH2:24][CH2:25][NH2:26])#[N:23]>O1CCCC1>[C:22]([CH2:24][CH2:25][NH:26][C:9]([C:7]1[C:6]2[CH:12]=[C:13]([C:16]([F:19])([F:18])[F:17])[CH:14]=[CH:15][C:5]=2[O:4][C:3]([CH2:2][F:1])([CH2:20][F:21])[CH:8]=1)=[O:10])#[N:23]
Reactant: O=C(O)C1=CC(CF)(CF)Oc2ccc(C(F)(F)F)cc21
Reactant: N#CCCN
Solvent: C1CCOC1
Product: N#CCCNC(=O)C1=CC(CF)(CF)Oc2ccc(C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.5 %

Procedure:
A mixture of 0.20 g of 2,2-bisfluoromethyl-6-trifluoromethyl-2H-1-benzopyran-4-carboxylic acid, 0.12 g of N,N-carbonyl diimidazole and 3 ml of tetrahydrofuran was stirred at room temperature for one hour. The reaction mixture was combined with 0.06 g of 2-cyanoethylamine and further stirred at room temperature for 14 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was subjected to silica gel column chromatography (eluent; ethyl acetate:hexane=1:1) to give 0.20 g of N-(2-cyanoethyl)-2,2-bisfluoromethyl-6-trifluoromethyl-2H-1-benzopyran-4-carbamide; m.p. 135-136° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].Br[CH2:10][C@H:11]([CH3:14])[CH2:12][Cl:13]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:10][C@H:11]([CH3:14])[CH2:12][Cl:13]
Reactant: C[C@H](CCl)CBr
Reactant: Oc1ccccc1Cl
Product: C[C@H](CCl)COc1ccccc1Cl

Procedure:
Prepared by Procedure U and Scheme AK using 2-chlorophenol and (2R)-1-bromo-3-chloro-2-methylpropane.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:35]([C:37]1([O:40]C(=O)C)[CH2:39][CH2:38]1)=[O:36]>>[OH:40][C:37]1([C:35]([N:2]2[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]3[C:15]4[N:16]=[CH:17][N:18]=[C:19]([C:20]5[C:28]6[O:27][CH2:26][O:25][C:24]=6[CH:23]=[CH:22][C:21]=5[O:29][CH2:30][CH:31]5[CH2:32][CH2:33]5)[C:14]=4[NH:13][CH:12]=3)=[O:10])[CH2:4][CH2:3]2)=[O:36])[CH2:39][CH2:38]1
Reactant: O=C(NC1CCNCC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Reactant: CC(=O)OC1(C(=O)Cl)CC1
Agent: Cl
Product: O=C(NC1CCN(C(=O)C2(O)CC2)CC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12

Procedure:
Starting from 4-(5-cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide hydrochloride (example A138) and acetic acid 1-chlorocarbonyl-cyclopropyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[BrH:10].BrBr>[H][H].BrBr>[BrH:10].[Br:10][CH2:2][C:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)=[O:3]
Reactant: CC(=O)c1ccncc1
Reactant: [H][H]
Agent: Br
Agent: BrBr
Product: O=C(CBr)c1ccncc1
Temperature: 70 °C
Reaction time: 2.5 h

Procedure:
4-Acetylpyridine (10 g) was combined with 48% hydrogen bromide solution (18 ml) and heated to 70° C. Bromine (4.7 ml) dissolved in 48% hydrogen bromine solution (5 ml) was then added dropwise and heating then continued for 2.5 h. The precipitate which formed was collected by filtration, washed with 1:1 methanol:hexane (20 ml) and dried in vacuo to give a cream solid (19.5 g) as 2:1 mixture of product:starting material by 1H nmr. mp 170-172° C.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]([N:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH2:21]([C:29]1([CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH3:67])[C:41]2[CH:40]=[C:39]([B:42]3[O:46][C:45]([CH3:48])([CH3:47])[C:44]([CH3:50])([CH3:49])[O:43]3)[CH:38]=[CH:37][C:36]=2[C:35]2[C:30]1=[CH:31][C:32](B1OC(C)(C)C(C)(C)O1)=[CH:33][CH:34]=2)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].CC(C)=O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.CCCCCC.O>[CH2:60]([C:29]1([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:30]2[CH:31]=[C:32]([C:2]3[CH:20]=[CH:19][C:5]([N:6]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)=[CH:4][CH:3]=3)[CH:33]=[CH:34][C:35]=2[C:36]2[C:41]1=[CH:40][C:39]([B:42]1[O:43][C:44]([CH3:49])([CH3:50])[C:45]([CH3:47])([CH3:48])[O:46]1)=[CH:38][CH:37]=2)[CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH3:67]
Reactant: CCCCCCCCC1(CCCCCCCC)c2cc(B3OC(C)(C)C(C)(C)O3)ccc2-c2ccc(B3OC(C)(C)C(C)(C)O3)cc21
Reactant: Brc1ccc(N(c2ccccc2)c2ccccc2)cc1
Agent: [Pd]
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Solvent: CCCCCC
Product: CCCCCCCCC1(CCCCCCCC)c2cc(B3OC(C)(C)C(C)(C)O3)ccc2-c2ccc(-c3ccc(N(c4ccccc4)c4ccccc4)cc3)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Bromo-N,N-diphenylaniline (19.44 g, 60 mmole), 2-[9,9-dioctyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9H-fluoren-2-yl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (76.9 g, 120 mmole), Aliquat™ 336 (tricaprylylmethylammonium chloride) (6 g, 15 mmole) and 2M sodium carbonate solution (75 mL, 150 mmole) were added to 600 mL of toluene. This was purged with a stream of nitrogen for about 30 min. Under a nitrogen purge, tetrakis(triphenylphosphine) palladium (0) (348 mg, 0.30 mmole) was added. The reaction mixture was then refluxed for 16 hrs. The reaction was cooled to room temperature and water added. The organic layer was separated and washed with water followed by brine. Drying of the organic layer over Na2SO4 and evaporation of the solvent gave a light yellow solid. This was suspended in acetone and the mixture brought to reflux and then allowed to stand at room temperature overnight. Filtration of the solid and concentration of the filtrate gave a solid that was subjected to column chromatography (toluene:hexane 3:7) to give 4-[9,9-dioctyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9H-fluoren-2-yl]-N,N-diphenylaniline.
Reaction SMILES: C([O:3]/[CH:4]=[CH:5]\[C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[C:13]1[CH:16]=[CH:17][C:18]([CH3:20])=[CH:19][C:12]1=[N:11][C:10]=2[NH2:21])C.Cl.C([O-])(O)=O.[Na+].[Li+].[B-](CC)(CC)CC.C1COCC1>O1CCOCC1>[NH2:21][C:10]1[C:9]2[N:8]=[CH:7][C:6]([CH2:5][CH2:4][OH:3])=[CH:15][C:14]=2[C:13]2[CH:16]=[CH:17][C:18]([CH3:20])=[CH:19][C:12]=2[N:11]=1
Reactant: CCO/C=C\c1cnc2c(N)nc3cc(C)ccc3c2c1
Agent: CC[B-](CC)CC
Agent: Cl
Agent: O=C([O-])O
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)nc(N)c1ncc(CCO)cc12
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A solution of (Z)-2-(2-ethoxyvinyl)-8-methylbenzo[f][1,7]naphthyridin-5-amine (from the previous step) in a mixture of 2:5 conc. HCl and dioxane (0.1 M) was heated at 60° C. overnight. Upon cooling down to rt, the reaction mixture was treated with excess NaHCO3 saturated solution, followed by extraction with EtOAc. Combined organic extracts were concentrated and was taken up in THF (0.2 M), and was treated with 1 N super hydride solution in THF (10 eq.) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction was worked up following the procedures described for Example 42/Step 3, to afford 2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethanol as white solid. 1H NMR (CDCl3): δ 8.61 (d, 1H), 8.47 (d, 1H), 8.01 (d, 1H), 7.41 (s, 1H), 7.10 (d, 1H), 6.40 (s, 1H), 6.01 (bs, 2H), 4.01 (t, 2H), 3.06 (t, 2H), 2.43 (s, 3H). LRMS [M+H]=254.1
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:10]2[S:15][CH2:14][CH2:13][CH2:12][S:11]2)[CH3:9])=[CH:4][CH:3]=1.C([Li])(CC)C.[Br:21][CH2:22][CH2:23][CH2:24][CH2:25]Br.C(OCC)(=O)C>O1CCCC1>[Br:21][CH2:22][CH2:23][CH2:24][CH2:25][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:10]2[S:15][CH2:14][CH2:13][CH2:12][S:11]2)[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(c1ccc(Br)cc1)C1SCCCS1
Reactant: BrCCCCBr
Agent: [Li]C(C)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(c1ccc(CCCCBr)cc1)C1SCCCS1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 4-bromo-1-(1,3-dithian-2-yl)ethylbenzene (27.2 g, 94 mmol) in tetrahydrofuran (200 ml) was charged with sec-butyllithium (99 ml, 1.3M in cyclohexane, 0.13 mole) dropwise at -78° C. under nitrogen. The mixture was stirred at ambient temperature for 1.5 hours, and then quenched with 1,4-dibromobutane (42 g, 0.2 mole). After being stirred for 3 hours, the mixture was poured into ethyl acetate, and then washed with water and brine. The organic solution was then dried (Na2SO4) and concentrated to an oil. The crude product was purified by flash chromatography over a silica gel column. The 4-(4-bromobutyl)-1-(1,3-dithian-2-yl)-ethylbenzene thus purified was a light oil, 22.3 g.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:12]([CH2:14][C:15](OCC)=[O:16])=O>C(O)(=O)C>[CH3:7][O:8][C:9]1[CH:10]=[C:11]([C:12]2[CH:14]=[C:15]([OH:16])[N:3]3[N:4]=[CH:5][CH:6]=[C:2]3[N:1]=2)[CH:20]=[CH:21][C:22]=1[O:23][CH3:24]
Reactant: CCOC(=O)CC(=O)c1ccc(OC)c(OC)c1
Reactant: Nc1cc[nH]n1
Solvent: CC(=O)O
Product: COc1ccc(-c2cc(O)n3nccc3n2)cc1OC
Yield: 41.5 %

Procedure:
3-Aminopyrazole (33.2 g) and 110 g of ethyl 3,4-dimethoxybenzoylacetate are stirred in 500 ml of glacial acetic acid for 6 hours at 80° C. After cooling the crystallized-out product is filtered off under suction, washed with diethyl ether and dried. There are obtained 45 g of 5-(3,4-dimethoxyphenyl)pyrazolo[1,5-a]pyrimidin-7-ol of m.p. 268°-270° C.
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][C@@H:3]([C:14]([OH:16])=[O:15])[NH:2]1.O=S(Cl)Cl.[CH2:21](O)[CH3:22]>>[CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][C@@H:3]([C:14]([O:16][CH2:21][CH3:22])=[O:15])[NH:2]1
Reactant: O=C(O)[C@@H]1Cc2c([nH]c3ccccc23)CN1
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)[C@@H]1Cc2c([nH]c3ccccc23)CN1
Yield: 68 %

Procedure:
(3S)-1,2,3,4-Tetrahydro-β-carboline-3-carboxylic acid (32.5 g) is suspended in ethanol (500 ml) and thereto is added dropwise SOCl2 (13.0 ml) at 0° C. The mixture is refluxed for 8 hours and then distilled to remove the solvent. The residue is dissolved in water and is made alkaline with NH4OH and extracted with ethyl acetate. The extract is dried and distilled to remove the solvent. The residue is recrystallized from ethyl acetate-isopropyl ether to give the title compound (24.86 g, 68%) as colorless needles, m.p. 135°-137° C.