Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[F:18])[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N+:12]([O-])=O>C(OCC)(=O)C.CO.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:6]2[C:7]([NH2:12])=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:15]=[CH:16][C:17]=1[F:18]
Reactant: O=[N+]([O-])c1ccccc1Nc1ccc(F)c(F)c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1ccccc1Nc1ccc(F)c(F)c1
Reaction time: 3 h
Yield: 50.7 %

Procedure:
A solution of 3,4-difluoro-N-(2-nitrophenyl)aniline (22.76 g, 91 mmol) in 50% ethyl acetate/methanol (500 mL) was treat with palladium on carbon 10 w. % loading, matrix activated carbon support (3.07 g). The reaction mixture was placed on the Parr shaker for 3 h at 60 psi. The reaction mixture was filtered through celite and evaporated. The crude reaction product was purified by flash chromatography (SiO2, 3→50% ethyl acetate/heptane) to provided N-(3,4-difluorophenyl)benzene-1,2-diamine (10.17 g, 51%) as a brown solid: HPLC purity 99.9% at 210-370 nm, 9.4 min.; Xterra RP18, 3.5 u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:40])[C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:23][CH2:22]2)=[N:17][CH:16]=1.[N+:41]([O-])([OH:43])=[O:42].C(OC(=O)C)(=O)C.C(=O)([O-])O.[Na+]>C(Cl)Cl>[O:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:40])[C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH2:23][CH2:22]2)=[N:17][CH:16]=1)[N+:41]([O-:43])=[O:42]
Reactant: O=[N+]([O-])O
Reactant: O=C(NCCCCCCCCCCCO)c1ccc(N2CCN(C(c3ccccc3)c3ccccc3)CC2)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: O=C(NCCCCCCCCCCCO[N+](=O)[O-])c1ccc(N2CCN(C(c3ccccc3)c3ccccc3)CC2)nc1
Reaction time: 6 h
Yield: 57 %

Procedure:
0.66 g of N-(11-hydroxy-1-undecanyl)-6-(4-diphenylmethyl-1-piperazinyl)nicotinamide were dissolved in 15 ml of methylene chloride and to the solution was added dropwise under ice-cooling a mixed solution of 0.2 ml of fuming nitric acid and 0.5 ml of acetic anhydride and stirred for 6 hrs. This reaction mixture was poured into an aqueous sodium hydrogencarbonate solution, extracted with methylene chloride, washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated. The concentrate was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give 0.41 g (57%) of the title compound.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.Cl.[N:12]1([C:18]2[CH:23]=[CH:22][N:21]=[C:20]3[NH:24][N:25]=[C:26]([O:27][CH2:28][CH:29]([OH:32])[CH2:30][OH:31])[C:19]=23)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.[C:33]([O:37][C:38]([NH:40][C@H:41]([CH2:45][C:46]1[CH:51]=[CH:50][C:49]([Cl:52])=[CH:48][CH:47]=1)[C:42](O)=[O:43])=[O:39])([CH3:36])([CH3:35])[CH3:34].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[Cl:52][C:49]1[CH:50]=[CH:51][C:46]([CH2:45][C@@H:41]([NH:40][C:38](=[O:39])[O:37][C:33]([CH3:35])([CH3:34])[CH3:36])[C:42]([N:15]2[CH2:16][CH2:17][N:12]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]4[NH:24][N:25]=[C:26]([O:27][CH2:28][CH:29]([OH:32])[CH2:30][OH:31])[C:19]=34)[CH2:13][CH2:14]2)=[O:43])=[CH:47][CH:48]=1
Reactant: OCC(O)COc1n[nH]c2nccc(N3CCNCC3)c12
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ccnc3[nH]nc(OCC(O)CO)c23)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
DIEA (0.0514 mL, 0.295 mmol) was added to 3-(4-(piperazin-1-yl)-1H-pyrazolo[3,4-b]pyridin-3-yloxy)propane-1,2-diol dihydrochloride (0.030 g, 0.0737 mmol, see Example 7), (R)-2-(tert-butoxycarbonylamino)-3-(4-chlorophenyl)propanoic acid (0.022 g, 0.074 mmol) and TBTU (0.0284 g, 0.0885 mmol) in DCM (1 mL) and stirred at room temperature for 1 hour. The reaction was concentrated to dryness. The resulting residue was dissolved in THF/MeOH (2 mL, 1:1), and a LiOH solution (1 mL, 2M) was added. The solution was stirred for 30 minutes. Ether (20 mL) was then added. The organic layer was separated, washed with brine (10 mL), and dried over sodium sulfate. After removal of solvent, the resulting residue was purified by chromatography (ethyl acetate:MeOH, 20:1) to give tert-butyl(2R)-3-(4-chlorophenyl)-1-(4-(3-(2,3-dihydroxypropoxy)-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazin-1-yl)-1-oxopropan-2-ylcarbamate as a solid. The solid was dissolved in DCM (1 mL), and TFA (0.4 mL) was added. The mixture was stirred at room temperature for 1 hour and then concentrated to dryness. The resulting residue was dissolved in DCM (0.5 mL), and HCl in ether (1 mL, 2N) was added. The resulting solid was collected by filtration to give (2R)-2-amino-3-(4-chlorophenyl)-1-(4-(3-(2,3-dihydroxypropoxy)-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazin-1-yl)propan-1-one (0.010 g, 25%). MS APCI (+) m/z 475.2 detected.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:10][C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][C:12]=1[Cl:18])[CH3:9].Cl[C:20](Cl)([O:22]C(=O)OC(Cl)(Cl)Cl)Cl>CCOC(C)=O>[CH2:8]([O:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]=[C:20]=[O:22])=[CH:13][C:12]=1[Cl:18])[CH3:9]
Reactant: CCOc1ccc(N)cc1Cl
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOc1ccc(N=C=O)cc1Cl

Procedure:
1-Ethoxy-2-chloro-4-isocyanato-benzene is prepared by addition of triethylamine to a solution of 4-ethoxy-3-chlorophenylamine in EtOAc at 0-5° C. Triphosgene is added and the reaction mixture is slowly heated to reflux over 2 h. The solvent is removed in vacuo and the crude product is filtered through silica to afford the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:3]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.B(F)(F)F.CCOCC.[OH-].[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]2[C:6](=[O:8])[C:17]3[C:12]([O:11][C:4]=2[CH:3]=1)=[CH:13][CH:14]=[CH:15][CH:16]=3
Reactant: O=C(O)c1ccc(Br)cc1Oc1ccccc1
Agent: FB(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: O=c1c2ccccc2oc2cc(Br)ccc12
Reaction time: 0.25 h

Procedure:
To a suspension of 4-bromo-2-phenoxybenzoic acid, 2a (35.1 g, 120 mmol) in. methylene chloride (350 mL) at 0° C. was added dropwise trifluoroacetic anhydride (20.3 mL, 144 mmol), and the reaction was stirred for 15 min. Boron trifluoride diethyl etherate (1.46 mL, 12.0 mmol) was added dropwise. The reaction became homogeneous upon stirring for 1 h at rt. The reaction was poured into 1 N NaOH, and the organic phase was dried over magnesium sulfate, filtered, and concentrated to give title compound 3-bromo-xanthen-9-one, 3a (32.14 g, 116 mmol). MS m/z (MH+) 275.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([CH:8]([CH3:10])[CH3:9])=[CH:6][CH:7]=1.Br[CH2:12][C:13](=O)[CH3:14].C(#N)C.[OH-].[Na+]>O>[CH:8]([C:5]1[CH:6]=[CH:7][C:2]2[N:3]([CH:12]=[C:13]([CH3:14])[N:1]=2)[N:4]=1)([CH3:10])[CH3:9]
Reactant: CC(=O)CBr
Reactant: CC(C)c1ccc(N)nn1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: Cc1cn2nc(C(C)C)ccc2n1

Procedure:
3-Amino-6-isopropylpyridazine (0.41 g, 2.99 mmol) and bromoacetone (0.53 g, 3.10 mmol) were mixed with acetonitrile (5.0 ml) and heated for 6 hours under reflux. After the reaction was completed, water (20.0 ml) was poured into the reaction solution and adjusted to pH 9 with 20% aqueous sodium hydroxide solution. The reaction solution was extracted twice with ethyl acetate, and the extracts were combined, dried over anhydrous sodium sulfate and concentrated. The residues were purified by silica gel column chromatography (ethyl acetate:chloroform=1:1) to give the title compound as brown oil. The yield was 0.30 g (57.2%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[NH:4][CH2:5][C@H:6]([CH2:11][C:12](=[O:22])[NH:13][C@H](C1C=CC=CC=1)C)[CH2:7][CH:8]([CH3:10])[CH3:9].O1CCCC1.N.[Na]>O>[CH3:1][O:2][C:3](=[O:23])[NH:4][CH2:5][C@H:6]([CH2:11][C:12](=[O:22])[NH2:13])[CH2:7][CH:8]([CH3:9])[CH3:10]
Reactant: COC(=O)NC[C@H](CC(=O)N[C@@H](C)c1ccccc1)CC(C)C
Agent: N
Agent: [Na]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)NC[C@H](CC(N)=O)CC(C)C
Yield: 60.5 %

Procedure:
A 2 1, four-necked flask, equipped with a mechanical stirrer, thermometer pocket and a liquid ammonia inlet, was charged with {(S)-4-methyl-2-[((S)-1-phenylethylcarbamoyl)-methyl]pentyl}carbamic acid methyl ester (26) (25 g, 0.078 mole), tetrahydrofuran (175 ml), and water (25 ml). The reaction mixture was cooled to −40° to −60° C. and liquid ammonia (1000 ml) was added followed by addition of small pieces of sodium metal (7.2 g). The resultant reaction mixture was stirred vigorously for 4-10 hours until the ammonia had evaporated. Water (100 ml) was added to the reaction mass under N2 atmosphere at 5°-10° C., followed by separating the phases. The organic layer was separated and dried over anhydrous sodium sulphate and the solvent was stripped off. The residue was crystallized from diisopropyl ether to get 10.2 g (60% yield) of {(S)-2-carbamoylmethyl-4-methylpentyl}carbamic acid methyl ester with purity of 73% as measured by HPLC.
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]1[C:18]([OH:21])([CH3:20])[CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:24]I.O>C1COCC1>[CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]1[C:18]([O:21][CH3:24])([CH3:19])[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: CC(C)(O)C1c2ccccc2CCN1Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(C)(C)C1c2ccccc2CCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
With cooling in an ice-MeOH bath under an argon atmosphere, a solution of 2-(2-benzyl-1,2,3,4-tetrahydroisoquinolin-1-yl)propan-2-ol (1.27 g) in THF (7 mL) was added dropwise to a solution of sodium hydride (60%, 199 mg) in THF (5 mL), followed by stirring at room temperature for 0.5 hours. Then, the reaction liquid was cooled in ice and methyl iodide (0.42 mL) was added thereto. The mixture was stirred at room temperature for 8 hours. To the mixture were added sodium hydride (60%, 199 mg) and methyl iodide (0.42 mL), followed by stirring at room temperature for 12 hours. Water was added to the reaction solution, followed by extraction with EtOAc. The extract was washed with saturated brine, dried over magnesium sulfate, filtered, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-EtOAc) to obtain 2-benzyl-1-(1-methoxy-1-methylethyl)-1,2,3,4-tetrahydroisoquinoline (1.17 g).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[Cl:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH2:20][NH2:21]>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:21][CH2:20][C:19]2[CH:22]=[CH:23][CH:24]=[CH:25][C:18]=2[Cl:17])[N:3]=1
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Reactant: NCc1ccccc1Cl
Solvent: CCN(CC)CC
Product: Clc1nc(NCc2ccccc2Cl)c2ncn(C3CCCC3)c2n1

Procedure:
2-Chloro-6-[(2-chlorobenzyl)amino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 2-chlorobenzylamine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[S:9](Cl)(=[O:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C1C=CC=CN=1)C.[O:22]1[C:26]2[CH:27]=[CH:28][C:29]([C:31]3[C:32]([O:44][CH3:45])=[N:33][N:34]([CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[C:35]=3[NH2:36])=[CH:30][C:25]=2[O:24][CH2:23]1>N1C=CC=CC=1>[O:22]1[C:26]2[CH:27]=[CH:28][C:29]([C:31]3[C:32]([O:44][CH3:45])=[N:33][N:34]([CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[C:35]=3[NH:36][S:9](/[CH:8]=[CH:7]/[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:11])=[O:10])=[CH:30][C:25]=2[O:24][CH2:23]1
Reactant: O=S(=O)(Cl)/C=C/c1ccccc1
Reactant: COc1nn(Cc2ccccc2)c(N)c1-c1ccc2c(c1)OCO2
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Product: COc1nn(Cc2ccccc2)c(NS(=O)(=O)/C=C/c2ccccc2)c1-c1ccc2c(c1)OCO2
Reaction time: 24 h
Yield: 72 %

Procedure:
(E)-2-phenylethensulfonyl chloride (138 mg) and dimethylaminopyridine (40 mg) were added at room temperature under an atmosphere of nitrogen to a solution of 4-(1,3-benzodioxol-5-yl)-1-benzyl-3-methoxy-1H-pyrazol-5-amine (Preparation 58) (100 mg) in anhydrous pyridine (3 ml). After 24 h, another portion of (E)-2-phenylethensulfonyl chloride (32 mg) was added and the reaction was stirred for 48 h before the mixture was concentrated under reduced pressure. To the beige solid was added an aqueous solution of HCl (1N, 10 ml) and the mixture was extracted with dichloromethane (3×10 ml). The organic fractions were combined, dried on sodium sulfate and concentrated under reduced pressure. The residue was dissolved in ethanol (5 ml) and an aqueous solution of sodium hydroxyde (2N, 2.25 ml) was added. The reaction was stirred overnight. The reaction mixture was then diluted with water (20 ml), acidified with an aqueous solution of HCl (2N) and the solution was extracted with ethyl acetate (3×15 ml). The combined organic fractions were washed with brine (15 ml), dried on sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica, 10 g) eluted with hexane:ethyl acetate (2:1) to yield the title compound as colourless oil (109 mg) which crystallises in a mixture of ether and ethyl acetate.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:13][N:12]=[N:11][C:10]=1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:17][N:18](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.CN>CN(C=O)C>[CH3:17][NH:18][C:14]([C:10]1[N:11]=[N:12][S:13][C:9]=1[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:16]
Reactant: CC(C)(C)OC(=O)Nc1snnc1C(=O)O
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1nnsc1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 5-tert-butoxycarbonylamino-[1,2,3]thiadiazole-4-carboxylic acid (0.66 g, 2.7 mmol) in DMF (10 ml) was treated with TBTU (1.16 g, 3.5 mmol), N,N-diisopropyl ethyl amine (2.29 ml, 13.5 mmol) and methylamine (1.75 ml, 2M THF solution) and stirred at ambient temperature for 5 h. The reaction mixture was partitioned between potassium hydrogen sulfate (30 ml, 10% aqueous solution) and ethyl acetate (60 ml) and extracted. The organic layer was washed with water and brine, and the aqueous phases were back-extracted with ethyl acetate. The combined organic phases were dried and the solvent was evaporated. The residue was suspended in dichloromethane, sucked off, and the filtrate was evaporated. The product was obtained after purification of the crude material by silica gel chromatography using a heptane/ethyl acetate gradient as colorless solid (0.23 g, 33%).
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12](OC(=O)C)(=O)[CH3:13]>>[Cl:11][C:10]1[C:2]2[N:1]=[C:12]([CH3:13])[O:5][C:4](=[O:6])[C:3]=2[CH:7]=[CH:8][CH:9]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1c(Cl)cccc1C(=O)O
Product: Cc1nc2c(Cl)cccc2c(=O)o1
Temperature: 25 °C

Procedure:
A solution of 2-amino-3-chlorobenzoic acid (4.93 g, 28.7 mmol) in acetic anhydride (15 mL) was refluxed for 3 h, then cooled to room temperature. The precipitated solid was filtered, and washed with hexane. The title compound was obtained as a brown solid (4.33 g). 1H NMR (500 MHz, CDCl3) δ 8.11 (d, J=8 Hz, 1H), 7.86 (d, J=8 Hz, 1H), 7.43 (t, J=8 Hz, 1H), 2.54 (s, 3H).
Reaction SMILES: [N:1]1([C:7]2[CH:19]=[C:18]([C:20]([O:22][CH3:23])=[O:21])[C:10]3[NH:11][C:12]([C:14]([F:17])([F:16])[F:15])=[N:13][C:9]=3[CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=1[Cl:39]>CN(C)C=O>[Cl:39][C:33]1[C:34]([Cl:38])=[CH:35][CH:36]=[CH:37][C:32]=1[CH2:31][N:13]1[C:9]2[CH:8]=[C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[CH:19]=[C:18]([C:20]([O:22][CH3:23])=[O:21])[C:10]=2[N:11]=[C:12]1[C:14]([F:17])([F:15])[F:16]
Reactant: Clc1cccc(CBr)c1Cl
Reactant: COC(=O)c1cc(N2CCOCC2)cc2nc(C(F)(F)F)[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(N2CCOCC2)cc2c1nc(C(F)(F)F)n2Cc1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 6.05 %

Procedure:
A mixture of methyl 5-(4-morpholinyl)-2-(trifluoromethyl)-1H-benzimidazole-7-carboxylate, prepared as described in Example 45 (1.5 g, 4.56 mmol) and potassium carbonate (1.889 g, 13.67 mmol) in N,N-Dimethylformamide (DMF) (10 mL) was stirred at rt for 10 min. After addition of 1-(bromomethyl)-2,3-dichlorobenzene (1.639 g, 6.83 mmol), the mixture was warmed to 80° C. and stirred for 3 h at this temperature. The resulting mixture was cooled to rt and poured over ice. The precipitate formed was collected by filtration and air dried to give crude product (2.2 g, 4.51 mmol, 99% yield) (91% pure). A portion of this material (230 mg) was purified by reverse phase-HPLC (25 to 95% AcCN in water, plus 0.1% TFA) to give the desired product (137.4 mg, 0.276 mmol, 6.05% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.65 (d, J=2.27 Hz, 1H), 7.61 (dd, J=8.08, 1.26 Hz, 1H), 7.48 (d, J=2.27 Hz, 1H), 7.24 (t, J=7.96 Hz, 1H), 6.25 (dd, J=7.83, 1.26 Hz, 1H), 5.77 (s, 2H), 3.93 (s, 3H), 3.68-3.81 (m, 4H), 3.13-3.24 (m, 4H). MS (ES+) m/e 488 [M+H]+.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([CH2:11][CH2:12][C:13]3[CH:22]=[C:21]4[C:16]([CH2:17][CH2:18][CH2:19][NH:20]4)=[CH:15][C:14]=3[O:23][CH3:24])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C=O.[C:27]([BH3-])#N.[Na+].C(O)(=O)C>C(#N)C.C(OCC)(=O)C>[O:4]1[C:5]2([CH2:6][CH2:7][N:8]([CH2:11][CH2:12][C:13]3[CH:22]=[C:21]4[C:16]([CH2:17][CH2:18][CH2:19][N:20]4[CH3:27])=[CH:15][C:14]=3[O:23][CH3:24])[CH2:9][CH2:10]2)[O:1][CH2:2][CH2:3]1
Reactant: [BH3-]C#N
Reactant: COc1cc2c(cc1CCN1CCC3(CC1)OCCO3)NCCC2
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1cc2c(cc1CCN1CCC3(CC1)OCCO3)N(C)CCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 49 %

Procedure:
196 mg of 7-(2-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)ethyl)-6-methoxy-1,2,3,4tetrahydroquinoline was dissolved in 5 ml of acetonitrile. Thereafter, 1 ml of 37% formalin, 190 mg of sodium cyanoborohydride, and 0.15 ml acetic acid were added to the reaction solution, and the obtained mixture was then stirred at room temperature for 1 hour. Thereafter, the reaction solution was diluted with ethyl acetate, and then washed with a saturated sodium bicarbonate aqueous solution and a saturated sodium chloride aqueous solution. The organic layer was dried over magnesium sulfate and then concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (hexane-ethyl acetate), so as to obtain 100 mg of the subject compound.
Reaction SMILES: [CH:1]1([C:5]#[N:6])[CH2:4][CH2:3][CH2:2]1.C([N-]C(C)C)(C)C.[Li+].[O:15]1[CH2:19][CH2:18][C:17](=[O:20])[CH2:16]1.CN(C)P(N(C)C)(N(C)C)=O>C1COCC1>[OH:20][C:17]1([C:1]2([C:5]#[N:6])[CH2:4][CH2:3][CH2:2]2)[CH2:18][CH2:19][O:15][CH2:16]1
Reactant: N#CC1CCC1
Reactant: O=C1CCOC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: N#CC1(C2(O)CCOC2)CCC1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 44.3 %

Procedure:
To a solution of cyclobutanecarbonitrile (405 mg, 5 mmol) in THF (7 ml) was added 2.0M lithium diisopropylamide (2.5 ml, 5 mmol) dropwise at −78° C. The reaction solution was stirred at −78° C. for 40 minutes, followed by the addition of a solution of dihydrofuran-3(2H)-one (473 mg, 5.5 mmol) in hexamethylphosphoramide (268 mg, 1.5 mmol). The mixture was warmed to room temperature and stirred for 3 hours. The reaction mixture was quenched with 1N aqueous HCl solution and extracted with EtOAc (3×20 mL). The combined organic phases were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (eluted with petroleum ether:EtOAc=20:1) to provide the title compound as a corloless oil (0.37 g, yield 44%). 1H NMR (400 MHz, CDCl3): δ 4.15-4.05 (m, 2H), 3.86 (d, J=10.0 Hz, 1H), 3.74 (d, J=9.6 Hz, 1H), 2.47-2.42 (m, 4H), 2.39-2.31 (m, 3H), 2.01-1.94 (m, 2H).
Reaction SMILES: O[CH:2]1[O:17][C:5]2=[C:6]([O:15][CH3:16])[C:7]3[O:12][C:11](=[O:13])[CH:10]=[CH:9][C:8]=3[CH:14]=[C:4]2[CH2:3]1>C(O)=O>[CH3:16][O:15][C:6]1[C:7]2[O:12][C:11]([CH:10]=[CH:9][C:8]=2[CH:14]=[C:4]2[CH:3]=[CH:2][O:17][C:5]=12)=[O:13]
Reactant: COc1c2c(cc3ccc(=O)oc13)CC(O)O2
Solvent: O=CO
Product: COc1c2occc2cc2ccc(=O)oc12

Procedure:
A solution of 52.2 g (0.223 mole) of crude 2-hydroxy-9-methoxy-2,3-dihydro-7H-furo[3,2-g][1]benzopyran-7-one in 900 ml of 98% formic acid was heated under argon at 100° for 45 min. The solvent was removed in vacuo and the dark residue crystallized. After drying on the high vac, the crude product, was taken up in the minimum amount of warm methylene chloride and filtered through an alumina column. Evaporation of fractions afforded pure methoxsalen, mp 145°-146°.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].C([O:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[CH:28]=[CH:27][C:26]([CH2:29][N:30]2[C:38]3[C:33](=[CH:34][C:35]([C:39](O)=[O:40])=[CH:36][CH:37]=3)[C:32]([CH3:42])=[C:31]2[CH3:43])=[CH:25][CH:24]=1)=[O:16])(C)(C)C>>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH:5][C:39]([C:35]1[CH:34]=[C:33]2[C:38](=[CH:37][CH:36]=1)[N:30]([CH2:29][C:26]1[CH:25]=[CH:24][C:23]([C:18]3[C:17]([C:15]([OH:16])=[O:14])=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:28][CH:27]=1)[C:31]([CH3:43])=[C:32]2[CH3:42])=[O:40]
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: NCc1ccccc1Cl
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)NCc3ccccc3Cl)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Steps 8-9, Example 1, using 2-chlorobenzylamine and 1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.