Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:22]([CH3:24])[CH3:23])[CH:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([N:17]4[CH2:21][CH2:20][CH2:19][CH2:18]4)[CH:12]=3)[C:3]=12.[CH3:25][N:26]1[CH:30]=[CH:29][C:28]([S:31]([NH2:34])(=[O:33])=[O:32])=[N:27]1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C1C=CC=CC=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:22]([N:8]1[C:4]2=[N:5][CH:6]=[CH:7][C:2]([NH:34][S:31]([C:28]3[CH:29]=[CH:30][N:26]([CH3:25])[N:27]=3)(=[O:33])=[O:32])=[C:3]2[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[CH:12]=2)=[CH:9]1)([CH3:24])[CH3:23]
Reactant: Cn1ccc(S(N)(=O)=O)n1
Reactant: CC(C)n1cc(-c2cccc(N3CCCC3)c2)c2c(Br)ccnc21
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(C)n1cc(-c2cccc(N3CCCC3)c2)c2c(NS(=O)(=O)c3ccn(C)n3)ccnc21
Temperature: 150 °C
Yield: 67.6 %

Procedure:
A mixture of 4-bromo-1-isopropyl-3-(3-(pyrrolidin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine (D15) (400 mg, 1.041 mmol), 1-methyl-1H-pyrazole-3-sulfonamide (D94) (252 mg, 1.561 mmol), cesium carbonate (678 mg, 2.082 mmol), Pd2(dba)3 (71.5 mg, 0.078 mmol) and 2-(dimethylamino)-2′-(dicyclohexylphosphino)biphenyl (61.4 mg, 0.156 mmol) in 1,4-dioxane (4.5 mL) was heated under an atmosphere of nitrogen in a microwave at 150° C. for 30 minutes. The mixture was then filtered through celite, washing with ethyl acetate, and evaporated to dryness. The residues were purified on silica eluting with cyclohexane and ethyl acetate (0-100%). The appropriate fractions were combined and evaporated to dryness producing an impure material (327 mg). This was purified via MDAP (acidic) twice. The appropriate fractions were combined and evaporated to dryness to give the title compounds (131 mg). LCMS (A): m/z (M+H)+ 465, C24H28N6O2S requires 464 (acidic).
Reaction SMILES: [CH3:1][CH:2]1[CH:8]([CH3:9])[CH2:7][N:6](C(OCC2C=CC=CC=2)=O)[CH2:5][CH2:4][N:3]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].[H][H]>C(OCC)(=O)C.[OH-].[OH-].[Pd+2]>[CH3:9][CH:8]1[CH:2]([CH3:1])[N:3]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:4][CH2:5][NH:6][CH2:7]1
Reactant: [H][H]
Reactant: CC1CN(C(=O)OCc2ccccc2)CCN(C(=O)OC(C)(C)C)C1C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CC1CNCCN(C(=O)OC(C)(C)C)C1C

Procedure:
To a solution of 1-3 (3.3 g, 9.1 mmol) in ethyl acetate (45 mL) was added 20% palladium hydroxide on carbon (256 mg) and the reaction was stirred at room temperature under balloon pressure of hydrogen gas overnight. The reaction was filtered through celite and concentrated in vacuo to afford 1-4.
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12]C)=[C:4]([C:14]([OH:16])=[O:15])[CH:3]=1>CC(O)=O>[F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[C:4]([C:14]([OH:16])=[O:15])[CH:3]=1
Reactant: COc1c(C(=O)O)cc(F)c2ccccc12
Solvent: CC(=O)O
Product: O=C(O)c1cc(F)c2ccccc2c1O
Temperature: 80 °C
Reaction time: 8 h
Yield: 81.4 %

Procedure:
To 10.1 g 4-fluoro-1-methoxynaphthalene-2-carboxylic acid 55 ml HBr/HOAc were added and the mixture was stirred and heated. After 30 min at 60° C. another 7.5 ml of hBr/HOAc were added, and after an additional 30 min at 80° C. the mixture was cooled to ambient temperature and left standing overnight. The reaction was then poured into ice/water and the precipitated solid was filtered and washed with water, followed by 1% ether in heptane and then by heptane. The solid was dried in vacuo at 40° C. to yield 7.7 g 4-fluoro-1-hydroxynaphthalene-2-carboxylic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:11][C:12](=[O:28])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)(=[O:21])=[O:20])[CH:14]=2)=[N:5][CH:6]=[C:7]([CH:9]=[CH2:10])[CH:8]=1.[H][H]>[C].[Pd].C(O)C>[CH2:9]([C:7]1[CH:8]=[C:3]([O:2][CH3:1])[C:4]([NH:11][C:12](=[O:28])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([N:22]3[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]3)(=[O:21])=[O:20])[CH:14]=2)=[N:5][CH:6]=1)[CH3:10]
Reactant: C=Cc1cnc(NC(=O)c2cccc(S(=O)(=O)N3CCCCC3)c2)c(OC)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCc1cnc(NC(=O)c2cccc(S(=O)(=O)N3CCCCC3)c2)c(OC)c1
Yield: 94 %

Procedure:
10% palladium-carbon (3.0 mg) as a catalyst was added to an ethanol (2.0 mL) solution of the compound (9.0 mg) obtained in Example 107, and stirred overnight in a hydrogen atmosphere at room temperature. The catalyst was removed through filtration, the solvent was evaporated off under reduced pressure, and the resulting residue was purified through silica gel column chromatography (methanol/chloroform=from 0% to 20%, gradient) to give the entitled compound (8.5 mg, 94%) as a colorless oily substance.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[CH3:19][O:20][C:21]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=1[CH2:29][C:30](O)=[O:31]>>[CH3:19][O:20][C:21]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=1[CH2:29][C:30]([NH:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18])=[O:31]
Reactant: COc1ccc(CC(=O)O)c(OC)c1
Reactant: Nn1nc(N2CCOCC2)c2ccccc2c1=O
Product: COc1ccc(CC(=O)Nn2nc(N3CCOCC3)c3ccccc3c2=O)c(OC)c1

Procedure:
The product of Example 1B and 2-(2,4-dimethoxyphenyl)acetic acid were treated using a method similar to that described in Example 111 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.31 (d, J=7.8 Hz, 1H), 8.03 (d, J=8.0 Hz, 1H), 7.97-8.00 (m, 1H), 7.89-7.92 (m, 1H), 7.22 (d, J=8.2 Hz, 1H), 6.56 (d, J=2.4 Hz, 1H), 6.51 (dd, J=8.2, 2.4 Hz, 1H), 3.82-3.84 (m, 4H), 3.80 (s, 3H), 3.76 (s, 3H), 3.53 (s, 2H), 3.06-3.14 (m, 4H); MS (ESI+) M/Z 425 (M+H)+.
Reaction SMILES: [OH:1][C:2]([CH3:8])([CH3:7])[C:3]([O:5]C)=[O:4].[H-].[Na+].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[O:19][CH:20]=[C:21]([CH2:23]Cl)[N:22]=2)=[CH:14][CH:13]=1.[Cl-].[NH4+].[OH-].[Na+]>CN(C)C=O.C(O)C.O>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[O:19][CH:20]=[C:21]([CH2:23][O:1][C:2]([CH3:8])([CH3:7])[C:3]([OH:5])=[O:4])[N:22]=2)=[CH:16][CH:17]=1
Reactant: ClCc1coc(-c2ccc(Cl)cc2)n1
Reactant: COC(=O)C(C)(C)O
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(OCc1coc(-c2ccc(Cl)cc2)n1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.6 %

Procedure:
A solution of 1.55 g (13.2 mmol) of methyl 2-hydroxy-2-methylpropionate in 4 ml of dimethylformamide was added during 1 hour to a stirred suspension of 0.53 g (13.2 mmol) of a 60% sodium hydride dispersion in mineral oil in 8 ml of dry dimethylformamide. The solution was stirred at room temperature for 1 hour and was then added slowly to a solution of 2 g (9.4 mmol) of 2-(4-chlorophenyl)-4-chloromethyl-oxazole in 4 ml of dry dimethylformamide at 0° C. under an argon atmosphere. The mixture was stirred at room temperature overnight and 2 ml of saturated aqueous ammonium chloride were then added. The majority of the solvent was removed by evaporation under reduced pressure and the residue was partitioned between 100 ml of diethyl ether and 100 ml of water. The organic phase was separated, washed with 100 ml of water and dried over magnesium sulphate. The organic solution was filtered and evaporated to give 2.7 g of a crude solid. This solid was dissolved in 100 ml of ethanol and 0.4 g (10 mmol) of sodium hydroxide in 5 ml of water was added. The solution was heated at reflux for 1 hour, cooled and the majority of the solvent was removed under reduced pressure. The solid residue was dissolved in 400 ml of water and extracted twice with 100 ml of diethyl ether each time. The aqueous phase was acidified to pH 2 with concentrated hydrochloric acid and extracted three times with 100 ml of dichloromethane each time. The combined dichloromethane extracts were dried over magnesium sulphate, filtered and evaporated to give a solid which was recrystallized from ethyl acetate. There were obtained 1.6 g (57%) of 2-[[2-(4-chlorophenyl)-4-oxazolyl]methoxy]-2-methylpropionic acid of melting point 144.5°-145° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:4][CH:3]=1.[CH3:17][S:18](Cl)(=[O:20])=[O:19].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[S:18]([CH3:17])(=[O:20])=[O:19])=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)CNc1ccc(Br)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CN(c1ccc(Br)cc1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 31.7 %

Procedure:
A solution of tert-butyl [(4-bromophenyl)amino]acetate (intermediate 1, 5.86 g, 20.5 mmol), methanesulfonyl chloride (2.58 g, 1.74 mL, 22.5 mmol), triethylamine (4.15 g, 5.71 mL, 41.0 mmol) and 4-dimethylaminopyridine (260 mg, 2.05 mmol) in dichloromethane (100 mL) was heated at reflux for 14 h. A second portion of methanesulfonyl chloride (2.58 g, 1.74 mmol, 22.5 mmol) was added and heating at reflux continued for a further 48 h. The reaction was cooled to room temperature and extracted with aqueous hydrochloric acid solution (1.0 M; 3×50 mL). The organic phase was dried (magnesium sulfate) and evaporated to dryness. The residue was chromatographed on silica gel (10% diethyl ether:cyclohexane) to give the title compound as a pale cream solid (2.37 g, 32%). LC/MS: 3.35 min; z/e 381 and 383, calcd (M+18) 381 and 383. 1H NMR (400 MHz: CDCl3): 7.55 (2H), 7.35 (2H), 4.30 (2H), 3.10 (3H), 1.45 (9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[CH2:15]([O:17][C:18]([C:20]1([CH2:35]I)[CH2:24][CH2:23][N:22]([C:25](=[O:34])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH3:33])[CH2:21]1)=[O:19])[CH3:16]>>[CH2:15]([O:17][C:18]([C:20]1([CH2:35][O:14][C:11]2[CH:12]=[CH:13][C:8]([C:5]3[N:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=3)=[CH:9][CH:10]=2)[CH2:24][CH2:23][N:22]([C:25](=[O:34])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH3:33])[CH2:21]1)=[O:19])[CH3:16]
Reactant: Oc1ccc(-c2ncc(Cl)cn2)cc1
Reactant: CCOC(=O)C1(CI)CCN(C(=O)c2ccccc2OC)C1
Product: CCOC(=O)C1(COc2ccc(-c3ncc(Cl)cn3)cc2)CCN(C(=O)c2ccccc2OC)C1

Procedure:
The title compound was prepared according to the method described for Preparation 29 using 4-(5-chloro-pyrimidin-2-yl)-phenol (Preparation 19) and 3-iodomethyl-1-(2-methoxy-benzoyl)-pyrrolidine-3-carboxylic acid ethyl ester (Preparation 15) to afford the racemate as a white solid (160 mg, 65.7%)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]([CH3:19])[C:16]([NH2:18])=[NH:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:21]N>>[CH3:21][NH:17][C:16](=[NH:18])[CH:15]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH3:19]
Reactant: CN
Reactant: CC(C(=N)N)c1ccccc1OCc1ccccc1
Agent: Cl
Product: CNC(=N)C(C)c1ccccc1OCc1ccccc1

Procedure:
N-Methyl-2-(2-benzyloxyphenyl)propionamidine was prepared by the method described in Example 88 for the synthesis of 2-(2-benzyloxy-phenyl) propionamidine using methylamine hydrochloride instead of ammonium hydrochloride.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[N:15][C:16]([C:17]([NH:19][C@@H:20]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:21]([OH:23])=[O:22])=[O:18])=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.O/[N:56]=[C:57](\[NH2:59])/[CH3:58]>CN(C=O)C.O>[NH2:59]/[C:57](=[N:56]\[O:22][C:21](=[O:23])[C@@H:20]([NH:19][C:17]([C:16]1[N:15]=[C:14]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9][C:10]=12)=[O:18])[C:24]([CH3:26])([CH3:27])[CH3:25])/[CH3:58]
Reactant: C/C(N)=N/O
Reactant: CC(C)(C)OC(=O)N1CCn2c(-c3ccccc3)nc(C(=O)N[C@H](C(=O)O)C(C)(C)C)c2C1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: C/C(N)=N/OC(=O)[C@@H](NC(=O)c1nc(-c2ccccc2)n2c1CN(C(=O)OC(C)(C)C)CC2)C(C)(C)C
Reaction time: 0.5 h

Procedure:
Intermediate 22B (0.25 g, 0.55 mmol) was dissolved in DMF and EDCI (0.17 g, 0.87 mmol) was added, followed by HOBt (0.12 g, 0.87 mmol). The resulting mixture was stirred for 30 min and (Z)—N′-hydroxy-acetimidamide (0.06 g, 0.82 mmol) was added and the mixture was stirred overnight. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed successively with water, 2N Na2CO3 solution and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was used in the next step without purification. LCMS (+ESI) m/z 1025.2 [2M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[C:5]2[CH3:18].C([O-])([O-])=O.[K+].[K+].[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.ClCCl>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([CH3:11])[C:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:5]3[CH3:18])=[CH:29][CH:28]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Cc1c(-c2ccccc2)n(C)c2ccc(Br)cc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1ccc(-c2ccc3c(c2)c(C)c(-c2ccccc2)n3C)cc1
Yield: 38 %

Procedure:
The desired product was prepared using a procedure similar to step 3 of example 3. Thus, 5-bromo-1,3-dimethyl-2-phenyl-1H-indole (1.358 g, 4.524 mmol) was reacted with aqueous 2M K2CO3 (4.5 ml), 4-methoxyphenylboronic acid (0.825 g, 5.429 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (0.074 g, 0.090 mmol) in dioxane (46 ml) to give the desired product (0.563 g, 1.719 mmol, 38%) as a white solid, mp 156-159° C. 1H NMR (DMSO-d6) δ 2.25 (s, 3H), 3.61 (s, 3H), 3.79 (s, 3H), 7.01 (d, J=8.7 Hz, 2H), 7.43-7.50 (m, 5H), 7.55 (t, J=7.8 Hz, 2H), 7.64 (d, J=8.7 Hz, 2H), 7.73 (s, 1H); [ESI(+)], m/z 328 (M+H)+.
Reaction SMILES: [C:1](#[N:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:10][OH:11].C([O-])([O-])=O.[K+].[K+].O>C(O)C>[OH:11][NH:10][C:1](=[NH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: N#Cc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: N=C(NO)c1ccccc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 305.6 %

Procedure:
Benzonitrile (1 ml, 9.79 mmol) was mixed with hydroxylamine hydrochloride (1.36 g, 1.96 mmol) and K2CO3 (2.71 g, 1.96 mmol) in anhydrous ethanol (15 ml). The solution was stirred at 80° C. for 16 hr. Water was added and the aqueous phase was extracted with EtOAc (3×), dried over MgSO4 and the volatiles removed in vacuo to give a viscous oil (816 mg, 5.99 mmol, 62%). The compound 10A was used for next step without any further purification. HPLC (4 minutes gradient) tR 0.62 min; MS m/z 137.06 [M+H]+.
Reaction SMILES: C(C1C=CC(N[N:10]=[C:11]2[C:16]3=[N:17][C:18]4[C:23]([C:24](=[O:25])[N:15]3[CH2:14][CH2:13][CH2:12]2)=[CH:22][CH:21]=[CH:20][CH:19]=4)=CC=1)#N.[OH-].[NH4+:27]>O>[C:24]([C:23]1[CH:22]=[C:21]2[C:12]3[CH2:13][CH2:14][N:15]4[C:24](=[O:25])[C:23]5[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=5[N:17]=[C:16]4[C:11]=3[NH:10][C:20]2=[CH:19][CH:18]=1)#[N:27]
Reactant: [NH4+]
Reactant: N#Cc1ccc(NN=C2CCCn3c2nc2ccccc2c3=O)cc1
Agent: [OH-]
Solvent: O
Product: N#Cc1ccc2[nH]c3c(c2c1)CCn1c-3nc2ccccc2c1=O
Yield: 92 %

Procedure:
1 g. of 6-[(4-Cyano-phenyl)-hydrazono]-6,7,8,9-tetrahydro-11H-pyrido[2,1-b]quinazoline-11-one is heated in 10 g. of polyphosphoric acid at 180° C. for 30 minutes. After cooling the reaction mixture is diluted with 40 ml. of water and the pH is adjusted to 5 by adding 25 V/W% ammonium hydroxide solution. The precipitated product is filtered, washed with water and dried. 0.88 g. (92%) of 10-cyano-7,8-dihydro-5H,13H-indolo[2',3';3,4]-pyrido[2,1-b]quinazoline-5-one are obtained which after recrystallization from dimethylformamide melts at 255° C.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.FC(F)(F)C(O)=O.[CH3:16][N:17]1[C:21]([CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)=[CH:20][CH:19]=[N:18]1>>[I:1][C:20]1[CH:19]=[N:18][N:17]([CH3:16])[C:21]=1[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:32])([F:31])[F:33])=[CH:26][CH:25]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Cn1nccc1CCc1ccc(C(F)(F)F)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cn1ncc(I)c1CCc1ccc(C(F)(F)F)cc1
Reaction time: 1 h
Yield: 101.7 %

Procedure:
N-iodosuccinimide (1.91 g) was added to a trifluoroacetic acid (15 mL) solution of 1-methyl-5-{2-[4-(trifluoromethyl)phenyl]ethyl}-1H-pyrazole (1.96 g) at a room temperature, and the obtained solution was then stirred for 1 hour. Thereafter, the reaction solution was concentrated under a reduced pressure, and the residue was then diluted with chloroform. The resultant was washed with a saturated sodium hydrogencarbonate aqueous solution/a 30% sodium thiosulfate aqueous solution (1:1). The organic layer was washed with a saturated saline, and was then dried over anhydrous magnesium sulfate, followed by vacuum concentration. The residue was purified by column chromatography (silica gel cartridge, hexane:ethyl acetate=70:30 to 50:50), so as to obtain the title compound (2.98 g) in the form of a colorless oily substance.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[N:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH:19]=[CH:20][C:21]2[N:30]=[C:29]3[C:24]([CH2:25][CH2:26][C:27](=[O:31])[NH:28]3)=[CH:23][CH:22]=2)[CH2:12][CH2:11]1>[Ni].CCO.C1COCC1>[Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[N:10]1[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]2[N:30]=[C:29]3[C:24]([CH2:25][CH2:26][C:27](=[O:31])[NH:28]3)=[CH:23][CH:22]=2)[CH2:14][CH2:15]1
Reactant: Cc1c(F)ccc(N2CCN(CCCC=Cc3ccc4c(n3)NC(=O)CC4)CC2)c1Cl
Agent: [Ni]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1c(F)ccc(N2CCN(CCCCCc3ccc4c(n3)NC(=O)CC4)CC2)c1Cl
Yield: 89.2 %

Procedure:
7-{5-[4-(2-Chloro-4-fluoro-3-methyl-phenyl)-piperazin-1-yl]-pent-1-enyl}-3,4-dihydro-1H-[1,8]naphthyridin-2-one (0.382 g, 0.862 mmol) was hydrogenated using Ra—Ni (0.5 g) in 1:1 EtOH/THF (50 mL) for 12 h. The reaction was filtered and concentrated. Purification by liquid chromatography (SiO2, 5% MeOH/CH2Cl2 to 7% MeOH/CH2Cl2) gave the title compound as a light yellow foam (342 mg, 0.769 mmol, 89%). MS: APCI: M+1: 445.2 (Exact Mass: 444.21).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=1)=[CH:10][CH:9]=2)=[O:5])[CH3:2].Br[C:26]1[CH:31]=[CH:30][C:29]([O:32][CH:33]2[CH2:35][CH2:34]2)=[CH:28][CH:27]=1>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH:33]3[CH2:35][CH2:34]3)=[CH:28][CH:27]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]1[CH:16]=[CH:17][C:18]([C:21]([CH3:23])([CH3:22])[CH3:24])=[CH:19][CH:20]=1)=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(-c3ccc(C(C)(C)C)cc3)ccc2[nH]1
Reactant: Brc1ccc(OC2CC2)cc1
Product: CCOC(=O)c1cc2cc(-c3ccc(C(C)(C)C)cc3)ccc2n1-c1ccc(OC2CC2)cc1

Procedure:
The sub-title compound was prepared in accordance with Example 1(b) from 5-(4-tert-butylphenyl)indole-2-carboxylic acid ethyl ester (see Example 1(a)) and 1-bromo-4-cyclopropoxybenzene (see step (c) above).
Reaction SMILES: [C:1]([C:4]1([CH2:17][CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)(=[O:3])[NH2:2]>FC(F)(F)C(O)=O>[C:1]([C:4]1([CH2:17][CH2:18][C:19]([OH:21])=[O:20])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=2[C:11]2[C:16]1=[CH:15][CH:14]=[CH:13][CH:12]=2)(=[O:3])[NH2:2]
Reactant: CC(C)(C)OC(=O)CCC1(C(N)=O)c2ccccc2-c2ccccc21
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)C1(CCC(=O)O)c2ccccc2-c2ccccc21
Yield: 80.4 %

Procedure:
A solution of 1.0 g (2 mM) of 9-carbamoyl-9-(2-tert.-butoxycarbonylethyl)fluorene (from Example 6) in 3 ml of trifluoroacetic acid was stirred at 25° C. for four minutes. The reaction mixture was concentrated to dryness by evaporation under reduced pressure to provide an oil. The oil was triturated with diethyl ether and dried to give 670 mg of 9-carbamoyl-9-(2-hydroxycarbonylethyl)fluorene. m.p. 191°-192° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11](OS(C(F)(F)F)(=O)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br-].[CH3:23][C:24]1[C:25]([Zn+])=[N:26][CH:27]=[CH:28][CH:29]=1>O1CCCC1.[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>[CH3:23][C:24]1[C:25]([C:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:13][CH:12]=2)=[N:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Reactant: Cc1cccnc1[Zn+]
Agent: [Pd]
Agent: [Br-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cccnc1C1=CCN(C(=O)OC(C)(C)C)CC1
Temperature: 70 °C
Yield: 82 %

Procedure:
A solution of 4-trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (8.10 g, 24.8 mmol; Bursavich, M. G.; et al. Org. Lett. 2001, 3, 2317) in tetrahydrofuran (50 mL) was treated with 3-methyl-2-pyridylzinc bromide (0.5 M in tetrahydrofuran, 65.0 mL, Aldrich), tetrakis(triphenylphosphine)-palladium(0) (280 mg, 0.24 mmol) and the mixture heated to 70° C. for 2 hours. The mixture was cooled to room temperature, concentrated under reduced pressure, the residue taken up in dichloromethane and washed with 1N sodium hydroxide. The organic phase was dried (magnesium sulfate), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (elution with 50% ethyl acetate: hexanes) to provide 5.50 g (82% yield) of the title compound as a light yellow oil. 1H NMR (300 MHz, DMSO-d6) δ 1.44 (s, 9H), 2.32 (s, 3H), 2.44 (m, 2H), 3.54 (m, 2H), 3.99 (m, 2H), 5.88 (br s, 1H), 7.17 (dd, 1H, J=7.8, 4.8 Hz), 7.62 (br d, 1H, J=7.5 Hz), 8.36 (dd, 1H, J=4.8, 1.7 Hz); MS (DCI/NH3) m/e 275 (M+H)+; 292 (M+NH4)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[F:12].O.NN.[C:16]([O-])(=O)[CH3:17].[Na+].C(I)C>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:16][CH3:17])(=[O:10])=[O:9])=[CH:4][C:3]=1[F:12]
Reactant: CC(=O)[O-]
Reactant: O=S(=O)(Cl)c1ccc(Br)c(F)c1
Agent: NN
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCI
Product: CCS(=O)(=O)c1ccc(Br)c(F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 64 %

Procedure:
To solution of 4-bromo-3-fluorobenzene-1-sulfonyl chloride (50 g, 0.184 mol) in THF (800 mL) at 0° C. was added hydrazine monohydrate (40-50%, 41.26 g, 0.644 mol) dropwise over 45 minutes. The reaction was stirred for 4 hours at room temperature and then the solvent was removed under reduced pressure to low volume. Heptane (100 mL) was added and the solid was filtered and washed several times with heptanes. The resulting solid was dissolved in ethanol (800 mL). Sodium acetate (90.56 g, 1.104 mol) and ethyl iodide (143.49 g, 0.92 mol) were added and the reaction heated to reflux for 18 hours. The reaction was allow to cool to room temperature, the solvent was removed under reduced pressure to 30% of the initial volume. The reaction mixture was diluted with water (500 mL) and extracted with CH2Cl2 (3×250 mL). The combined organic layers were washed with brine (2×300 mL), dried over Na2SO4, filtered and reduced to dryness to give a yellow oil. The crude was absorbed onto silica and purified (using siica gel column chromatography eluting with cyclohexane/EtOAc 8/2 to give the title compound as yellow solid in 64% yield, 31.70 g.