Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][O:11][C:12]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:13]=2[CH:14]=[C:15]([C:21](O)=[O:22])[NH:16]3)=[CH:2]1.Cl.Cl.Cl.[NH2:27][CH:28]1[CH2:33][CH2:32][N:31]([CH2:34][C@@H:35]([N:37]2[CH2:42][CH2:41][C@H:40]([OH:43])[C@@H:39]([CH3:44])[CH2:38]2)[CH3:36])[CH2:30][CH2:29]1>>[OH:43][C@H:40]1[CH2:41][CH2:42][N:37]([C@@H:35]([CH3:36])[CH2:34][N:31]2[CH2:32][CH2:33][CH:28]([NH:27][C:21]([C:15]3[NH:16][C:17]4[C:13]([CH:14]=3)=[C:12]([O:11][CH2:10][C:3]3[C:4]5[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=5[O:1][CH:2]=3)[CH:20]=[CH:19][CH:18]=4)=[O:22])[CH2:29][CH2:30]2)[CH2:38][C@@H:39]1[CH3:44]
Reactant: C[C@H]1CN([C@@H](C)CN2CCC(N)CC2)CC[C@@H]1O
Reactant: O=C(O)c1cc2c(OCc3coc4ccccc34)cccc2[nH]1
Agent: Cl
Product: C[C@H]1CN([C@@H](C)CN2CCC(NC(=O)c3cc4c(OCc5coc6ccccc56)cccc4[nH]3)CC2)CC[C@@H]1O

Procedure:
This compound is synthesized analogously to example 1 from 4-(benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid, 105 (see example 50) and amine 56.
Reaction SMILES: FC1C(F)=CC=CC=1[C@@H]1CC[C@@H](CC([N:23]2[CH2:28][CH2:27][CH:26]([N:29]3[C:37]4[C:32](=[N:33][CH:34]=[CH:35][CH:36]=4)[NH:31][C:30]3=[O:38])[CH2:25][CH2:24]2)=O)C2=NC=CC=C2C1.FC1C(F)=CC=CC=1[C@H]1CC[C@H](CC(N2CCC(N3C4C(=NC=CC=4)NC3=O)CC2)=O)C2=NC=CC=C2C1.Cl>C(Cl)Cl>[NH:23]1[CH2:24][CH2:25][CH:26]([N:29]2[C:37]3[C:32](=[N:33][CH:34]=[CH:35][CH:36]=3)[NH:31][C:30]2=[O:38])[CH2:27][CH2:28]1
Reactant: O=C(C[C@@H]1CC[C@@H](c2cccc(F)c2F)Cc2cccnc21)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Agent: Cl
Agent: O=C(C[C@H]1CC[C@H](c2cccc(F)c2F)Cc2cccnc21)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Solvent: ClCCl
Product: O=c1[nH]c2ncccc2n1C1CCNCC1

Procedure:
1-(1-(2-((6R,9S)-6-(2,3-Difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)acetyl)piperidin-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one and 1-(1-(2-((6S,9R)-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)acetyl)piperidin-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one. In a 100 mL round-bottomed flask was 2-((6,9-trans)-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)acetic acid (46.0 mg, 0.145 mmol) and 1-(piperidin-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one (95 mg, 0.435 mmol) (bis-HCl salt) in CH2Cl2 (4 ml) to give a colorless suspension. Hunig's Base (0.127 ml, 0.725 mmol) and 3-(DIETHOXYPHOSPHORYLOXY)-1,2,3-BENZO-TRIAZIN-4(3H)-ONE (87 mg, 0.290 mmol) were added. The reaction mixture was diluted with DMF (1 ml). Most solids were dissolved. It was stirred at rt overnight. 44 h: LCMS indicated complete conversion. It was diluted with EtOAc and washed with water. The layers were separated. The organic layer was washed with brine, dried with Na2SO4, and concentrated to a tan oil/gel. Purification by FCC (ISCO) up to 8% MeOH in CH2Cl2 afforded the desired product as a tan foam (68 mg, 86% for 2 steps). MS (ESI)[M+H+]=518.27; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 11.44 (br. s., 1H) 8.25-8.42 (m, 1H) 8.05 (d, J=5.29 Hz, 1H) 7.38 (t, J=8.44 Hz, 1H) 7.20-7.31 (m, 1H) 6.83-7.10 (m, 5H) 4.87 (d, J=12.34 Hz, 1H) 4.53-4.73 (m, 1H) 4.43 (t, J=15.36 Hz, 1H) 3.81-4.00 (m, 1H) 3.36-3.60 (m, 2H) 3.24 (t, J=12.97 Hz, 1H) 2.94 (t, J=11.21 Hz, 1H) 2.33-2.80 (m, 4H) 2.05-2.31 (m, 3H) 1.80-2.05 (m, 3H) 1.38-1.63 (m, 1H). The racemic product was resolved by chiral HPLC (Chiralpak AD-H analytical column, 4.6×250 mm, 5 μm; Mobile Phase: 40% MeOH in CO2; Temp: 35° C.; Flow rate: 2.0 mL/min. for 26 min; Injection: 5 uL of ˜2 mg/mL in MeOH). Compound (6R,9S) was the first peak with tR=13.88 min while compound (6S,9R) was the second peak with tR=19.19 min).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([CH2:13][NH2:14])=[C:11]([CH3:15])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl[C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][N:18]=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[CH3:24][O:23][C:21](=[O:22])[C:20]1[CH:25]=[CH:26][C:17]([NH:14][CH2:13][C:12]2[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:9][O:10][C:11]=2[CH3:15])=[N:18][CH:19]=1
Reactant: Cc1onc(-c2cccc(F)c2)c1CN
Reactant: COC(=O)c1ccc(Cl)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: COC(=O)c1ccc(NCc2c(-c3cccc(F)c3)noc2C)nc1
Temperature: 160 °C
Yield: 37.7 %

Procedure:
A mixture of C-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-methylamine (530 mg, 2.6 mmol), methyl 6-chloronicotinate (440 mg, 2.6 mmol), N,N-diisopropyl ethyl amine (880 μL, 5.1 mmol) and DMSO (5.1 mL) was heated in the microwave to 160° C. for 2×0.5 h and 1 h. The mixture was then diluted with ice-water and extracted with ethyl acetate. The combined organic extracts were then washed with brine and dried over sodium sulfate. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:1) afforded the title compound (335 mg, 38%) as a yellow gum. MS: m/e=342.1 [M+H]+.
Reaction SMILES: [CH2:1]([N:4](C)[CH2:5][C@@H:6]([CH3:34])[O:7][C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[C:10]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)=[C:21]([Cl:33])[CH:20]=1)=[N:11][CH:12]=[N:13]2)C=C>C(#N)C.O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh]>[Cl:33][C:21]1[CH:20]=[C:19]([NH:18][C:10]2[C:9]3[C:14](=[CH:15][CH:16]=[CH:17][C:8]=3[O:7][C@H:6]([CH3:34])[CH2:5][NH:4][CH3:1])[N:13]=[CH:12][N:11]=2)[CH:24]=[CH:23][C:22]=1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1
Reactant: C=CCN(C)C[C@@H](C)Oc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: O
Product: CNC[C@@H](C)Oc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Yield: 15 %

Procedure:
5-{(1R)-2-[allyl(methyl)amino]-1-methylethoxy}-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]quinazolin-4-amine was heated in acetonitrile/water in the presence of chlorotris(triphenylphosphine)rhodium (I) using an analogous procedure to that described below in Example 4-11 (preparation of starting materials) to give N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[(1R)-1-methyl-2-(methylamino)ethoxy]quinazolin-4-amine in 15% yield; Mass spectrum M+ 450.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][C@H:15]2[CH2:20][CH2:19][CH2:18][NH:17][CH2:16]2)[C:6]=1[C:7]#[N:8])([O-:4])=[O:3].C(N(CC)CC)C.[C:28](O)(=[O:32])[CH2:29][CH2:30][CH3:31].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl.CN(C=O)C>[C:28]([N:17]1[CH2:18][CH2:19][CH2:20][C@H:15]([CH2:14][O:13][C:9]2[CH:10]=[CH:11][CH:12]=[C:5]([N+:2]([O-:4])=[O:3])[C:6]=2[C:7]#[N:8])[CH2:16]1)(=[O:32])[CH2:29][CH2:30][CH3:31]
Reactant: CCCC(=O)O
Reactant: N#Cc1c(OC[C@H]2CCCNC2)cccc1[N+](=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCC(=O)N1CCC[C@H](COc2cccc([N+](=O)[O-])c2C#N)C1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a suspension of (S)-2-nitro-6-(piperidin-3-ylmethoxy)benzonitrile hydrochloride (Example 1d, 9.8 g, 32.92 mmol) in CH2Cl2 (550 mL) and DMF (50 mL) was added triethylamine (9.2 mL, 65.84 mmol). After being stirred at room temperature for 5 min., a solution of butyric acid (3.33 mL, 36.21 mmol), EDCI (6.94 g, 36.21 mmol) and HOBt (4.89 g, 36.21 mmol) in DCM (50 mL) was added, and the reaction mixture was then stirred at room temperature overnight. The resulting mixture was diluted with CH2Cl2, washed with 0.5 N HCl, water, NaHCO3 and brine, dried over MgSO4, filtered and evaporated to give the crude product as a light brown gel, used as this in the next step. MS 332 (MH+).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:32]=[CH:31][C:12]([C:13]([N:15]2[CH2:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[N:18]([CH2:26][C:27]([OH:29])=O)[C:17](=[O:30])[CH2:16]2)=[O:14])=[CH:11][CH:10]=1.[NH2:33][C:34]1[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=1.C(N(CC)CC)C>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([N:15]2[CH2:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[N:18]([CH2:26][C:27]([NH:33][C:34]3[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=3)=[O:29])[C:17](=[O:30])[CH2:16]2)=[O:14])=[CH:31][CH:32]=1
Reactant: Nc1ccncc1
Reactant: O=C(O)CN1C(=O)CN(C(=O)c2ccc(Cl)cc2)Cc2ccccc21
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(CN1C(=O)CN(C(=O)c2ccc(Cl)cc2)Cc2ccccc21)Nc1ccncc1
Reaction time: 8 h

Procedure:
20 mg (0.042 mmol) of [4-(4-chlorobenzoyl)-2-oxo-2,3,4,5-tetrahydrobenzo[e][1,4]diazepin-1-yl]acetic acid trifluoroacetate was dissolved in 2 ml of dichloromethane. 5 mg (0.055 mmol) of 4-aminopyridine, 11 mg (0.055 mmol) of 2-chloro-1,3-dimethylimidazonium chloride and 0.018 ml (0.126 mmol) of triethylamine were added to the obtained solution, and they were stirred overnight. The solvent was evaporated, and the obtained crude product was treated in the same manner as in step 3 in Example 1 to obtain the title compound.
Reaction SMILES: [CH3:1][S-:2].[Na+].Cl[CH2:5][C:6]1[N:7]([CH2:32][CH2:33][CH3:34])[C:8]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([S:24](=[O:31])(=[O:30])[NH:25][CH2:26][CH2:27][O:28][CH3:29])=[CH:20][CH:19]=3)[N:12]=2)=[CH:9][N:10]=1.[CH3:35]O>>[CH3:1][S:2][CH2:5][C:6]1[N:7]([CH2:32][CH2:33][CH3:34])[C:8]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([S:24](=[O:31])(=[O:30])[NH:25][CH2:26][CH2:27][O:28][CH2:29][CH3:35])=[CH:20][CH:19]=3)[N:12]=2)=[CH:9][N:10]=1
Reactant: CO
Reactant: CCCn1c(-c2ccnc(Nc3ccc(S(=O)(=O)NCCOC)cc3)n2)cnc1CCl
Reactant: C[S-]
Agent: [Na+]
Product: CCCn1c(-c2ccnc(Nc3ccc(S(=O)(=O)NCCOCC)cc3)n2)cnc1CSC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Sodium thiomethoxide (21 mg, 0.3 mmol) was added to a stirred solution of 4-[2-(chloromethyl)-1-(propyl)imidazol-5-yl]-2-{4-[N-(2-methoxyethyl)sulphamoyl]anilino}pyrimidine (Method 116; 52 mg, 0.1 mmol) in MeOH (5 ml) and the solution was stirred at ambient temperature for 3 hour. The solvent was removed evaporation and the residue was partitioned between water and EtOAc. The organic phase was washed with saturated aqueous sodium hydrogen carbonate solution and brine, dried (Na2SO4) and the volatiles removed by evaporation. The residue was triturated with ether and collected by filtration. This solid was suspended in MeOH (2 ml) and 1.0M ethereal hydrogen chloride was added to give a clear solution. The volatiles were removed by evaporation and the residue triturated with ether giving the title compound (42 mg, 80%) as the hydrochloride salt. NMR: 0.72 (t, 3H), 1.06 (t, 3H), 1.63 (m, 2H), 2.18 (s, 3H), 2.88 (q, 2H), 3.35 (m, 4H), 4.42 (s, 2H), 4.72 (m, 2H), 7.37 (d, 1H), 7.54 (t, 1H), 7.75 (d, 2H), 7.89 (d, 2H), 8.39 (s, 1H), 8.68 (d, 1H), 10.14 (s, 1H); m/z 491.
Reaction SMILES: [Li+].[CH2:2]([O:4][P:5]([O:19][CH2:20][CH3:21])([CH:7]([S:15]([O-:18])(=[O:17])=[O:16])[CH2:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)=[O:6])[CH3:3].C([Li:26])CCC.C(O)(=[O:29])C>O1CCCC1>[Li+:26].[CH2:2]([O:4][P:5]([O:19][CH2:20][CH3:21])([C:7]([OH:29])([S:15]([O-:18])(=[O:17])=[O:16])[CH2:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)=[O:6])[CH3:3]
Reactant: [Li]CCCC
Reactant: CC(=O)O
Reactant: CCOP(=O)(OCC)C(Cc1cccnc1)S(=O)(=O)[O-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)C(O)(Cc1cccnc1)S(=O)(=O)[O-]

Procedure:
A suspension of 3.29 g (0.01 mole) of 1-diethoxyphosphinyl-2-(3-pyridinyl)ethanesulfonic acid lithium salt (from part I of Example 16) in 50 ml of anhydrous tetrahydrofuran is stirred in a -40° bath under a dry nitrogen atmosphere. To this is added n-butyl lithium (4.4 ml of 2.5M solution in hexanes; 0.011 mole) via syringe over 5 minutes. The reaction mixture is allowed to warm to -15° , and is stirred at this temperature for about one hour. It is then cooled to -78°, and to it is added dropwise a solution of 3.44 g (0.015 mole) of camphorylsulfonyloxaziridine (J. Am. Chem. Soc., 112, 6679(1990)) in 50 ml of anhydrous THF. The reaction mixture is stirred for a few minutes at -78°, and then is placed in an ice/water bath. It is stirred at 0° for 2-10 minutes, and then is again cooled to -78° . The reaction mixture is quenched by addition of 1.2 g (0.02 mole) of acetic acid and the solvents are removed under vacuum on a rotary evaporator. The residue was purified by chromatography on silica gel using chloroform/methanol as eluant, to yield 1-diethoxyphosphinyl-1-hydroxy-2-(3-pyridinyl)ethanesulfonic acid lithium salt.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(O[N:24]=[C:25]([C:31]#[N:32])[C:26]([O:28][CH2:29][CH3:30])=[O:27])(=O)=O.C(N(CC)CC)C>C(OCC)(=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([O:15][N:24]=[C:25]([C:31]#[N:32])[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: CCOC(=O)C(C#N)=NOS(C)(=O)=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C#N)=NOC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.9 %

Procedure:
N-Benzyloxycarbonyl-L-proline (1.25 g) and ethyl 2-methanesulfonyloxyimino-2-cyanoacetate (1.1 g) are dissolved in ethyl acetate (10 ml). To the solution is added triethylamine (0.7 ml) and the mixture is stirred at room temperature for 1 hour. After allowing to stand overnight, to the reaction mixture is added ethyl acetate. The mixture is washed with water and dried over anhydrous magnesium sulfate. After drying, the solvent is distilled off to give ethyl 2-(N-benzyloxycarbonyl-L-prolyloxyimino)-2-cyanoacetate (1.9 g) as an oily substance.
Reaction SMILES: CC[O-].[Na+].Cl.[CH:6]1([NH:11][C:12]([NH2:14])=[NH:13])[CH2:10][CH2:9][CH2:8][CH2:7]1.[Cl:15][C:16]1[N:21]2[N:22]=[C:23]([C:29]3[O:30][CH:31]=[CH:32][C:33]=3[CH3:34])[C:24]([C:25](=O)[C:26]#[CH:27])=[C:20]2[CH:19]=[CH:18][CH:17]=1>C(O)C>[Cl:15][C:16]1[N:21]2[N:22]=[C:23]([C:29]3[O:30][CH:31]=[CH:32][C:33]=3[CH3:34])[C:24]([C:25]3[CH:26]=[CH:27][N:14]=[C:12]([NH:11][CH:6]4[CH2:10][CH2:9][CH2:8][CH2:7]4)[N:13]=3)=[C:20]2[CH:19]=[CH:18][CH:17]=1
Reactant: N=C(N)NC1CCCC1
Reactant: C#CC(=O)c1c(-c2occc2C)nn2c(Cl)cccc12
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1ccoc1-c1nn2c(Cl)cccc2c1-c1ccnc(NC2CCCC2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.6 %

Procedure:
Sodium ethylate solution (21% T, 0.5 mL, 1.43 mmol) was added to ethanol followed by cyclopentylguanidine hydrochloride (323 mg, 1.98 mmol). The mixture was stirred at room temperature for 30 minutes. 1-[7-Chloro-2-(3-methyl-2-furyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-one (313 mg, 1.10 mmol) was added to the resultant solution and stirred at room temperature for 15 hours. The reaction mixture was concentrated. Ethyl acetate and water were added to the residue. The phases were separated, the organic phase dried (magnesium sulfate), filtered and concentrated. The residue was recrystallized from ethyl acetate. 4-[7-Chloro-2-(3-methyl-2-furyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine (280 mg, 65%) was obtained as a yellow solid. 1H-NMR (CDCl3): δ 8.50 (d, 1H), 8.15 (d, 1H), 7.49 (d, 1H), 7.27 (t, 1H), 7.06 (d, 1H), 6.41 (d, 1H), 6.36 (d, 1H), 5.10 (d, 1H), 4.35 (m, 1H), 2.12 (s, 3H), 2.08 (m, 2H), 1.78–1.53 (m, 6H). MS m/z 394 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[CH:11]2[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.[ClH:31].CCCCCC>C(Cl)Cl>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[ClH:31]
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCc3ccc(F)cc32)CC1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCCCCC
Solvent: ClCCl
Product: Fc1ccc2c(c1)N(C1CCNCC1)CC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl 4-(6-fluoroindolin-1-yl)piperidine-1-carboxylate (16.64 g, 52 mmol) in CH2Cl2 (45 mL) was added TFA (30 mL) slowly at room temperature. The resulting mixture was stirred at room temperature for 3 h. The resulting mixture was concentrated to remove most of solvent and TFA. The resulting residue was partitioned in CH2Cl2/H2O (100 mL/50 mL) and stirred. 3N NaOH(aq) was added slowly until the pH value of aqueous layer was >11. The aqueous layer was then extracted with CH2Cl2 (100 mL×10). The combined CH2Cl2 layer was dried (Na2SO4) and filtered. The solvent was removed by roto-evaporator, the resulting residue was dissolved in Et2O (100 mL) and 1N HCl (1M in Et2O, 60 mL, 60 mmol) was added slowly at 0° C. Then, the resulting mixture was allowed to warm to room temperature for another 30 min. Hexane (100 mL) was added and stirred for 15 min. The resulting white solid was filtered and washed with 50% Et2O/hexane (30 mL×3), then dried to yield 6-fluoro-1-(piperidin-4-yl)indoline as a white HCl salt.
Reaction SMILES: O=C1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3]1.[CH:10]([O:15][CH3:16])([O:13][CH3:14])OC.[C:17](Cl)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>CO.CCCCC>[CH3:16][O:15][C:10]1([O:13][CH3:14])[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH3:17])=[O:8])[CH2:3]1
Reactant: COC(OC)OC
Reactant: O=C1CCC(C(=O)O)C1
Reactant: CC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCC
Solvent: CO
Product: COC(=O)C1CCC(OC)(OC)C1
Reaction time: 120 h
Yield: 105.1 %

Procedure:
(Tetrahedron, (1977), 33, 1113) A solution of 3-oxocyclopentanecarboxylic acid (10.013 g, 78 mmol) and trimethyl orthoformate (60.5 mL, 547 mmol) in MeOH (120 mL) was treated with acetyl chloride (7.78 mL, 109 mmol) and stirred under a nitrogen atmosphere for 5 days. The reaction solution was poured into a stirred suspension of anhydrous sodium carbonate (32 g) in pentane (250 mL) and stirred for 3 hrs. The solids were removed by filtration (2×) and concentrated under reduced pressure to give the target compound (15.4 g, 82 mmol, 105% yield) as a pale yellow oil. 1H NMR (500 MHz, CDCl3) δ ppm 3.67 (3 H, s), 3.20 (3 H, s), 3.18 (3 H, s), 2.82-2.93 (1 H, m), 2.01-2.15 (2 H, m), 1.77-2.01 (4 H, m).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:13]([CH3:14])[C:12]2[CH:15]=[CH:16][C:17]([N:19]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([Cl:27])[N:22]=3)[CH3:20])=[CH:18][C:11]=2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:28][C:29]1[CH:30]=[C:31]([S:35]([NH2:38])(=[O:37])=[O:36])[CH:32]=[CH:33][CH:34]=1>>[ClH:27].[CH2:1]([NH:8][C:9]1[N:13]([CH3:14])[C:12]2[CH:15]=[CH:16][C:17]([N:19]([CH3:20])[C:21]3[CH:26]=[CH:25][N:24]=[C:23]([NH:28][C:29]4[CH:30]=[C:31]([S:35]([NH2:38])(=[O:36])=[O:37])[CH:32]=[CH:33][CH:34]=4)[N:22]=3)=[CH:18][C:11]=2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccc(S(N)(=O)=O)c1
Reactant: CN(c1ccc2c(c1)nc(NCc1ccccc1)n2C)c1ccnc(Cl)n1
Product: CN(c1ccc2c(c1)nc(NCc1ccccc1)n2C)c1ccnc(Nc2cccc(S(N)(=O)=O)c2)n1
Product: Cl

Procedure:
The title compound was prepared following the procedure of Example 1 with N2-benzyl-N5-(2-chloropyrimidin-4-yl)-N5,1-dimethyl-1H-benzimidazole-2,5-diamine (95 mg, 0.25 mmol) and 3-amino-benzenesulfonamide (43 mg, 0.25 mmol) as a light pink solid (112 mg, 82%). 1H NMR (300 MHz, d6-DMSO+NaHCO3) δ 10.03 (br s, 2H), 9.55 (br s, 1H), 8.48 (s, 1H), 7.89 (d, J=6.3 Hz, 1H), 7.74 (m, 1H), 7.59 (d, J=8.7 Hz, 1H), 7.51 (m, 2H), 7.22-7.41 (m, 8H), 5.76 (d, J=6.3 Hz, 1H), 4.76 (d, J=5.7 Hz, 2H), 3.763 (s, 3H), 3.48 (s, 3H). MS (ESI) m/z=515 [M+H]+.
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[CH:30][CH:29]=2)=[CH:24][CH:23]=1>C(OCC)(=O)C>[Br-:20].[CH2:34]([C:31]1[CH:32]=[CH:33][C:28]([C:25]2[CH:26]=[CH:27][C:22]([CH2:21][P+:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:23][CH:24]=2)=[CH:29][CH:30]=1)[CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: CCCCCc1ccc(-c2ccc(CBr)cc2)cc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Product: CCCCCc1ccc(-c2ccc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)cc2)cc1
Product: [Br-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 55.5 %

Procedure:
A solution of 11.6 g of triphenylphosphine in 20 ml of ethyl acetate was placed in a sulphonation flask under argon gasification and treated at room temperature within 10 minutes with a solution of 7.5 g of 4-(bromomethyl)-4'-pentylbiphenyl in 15 ml of ethyl acetate. The reaction mixture was subsequently stirred at room temperature for a further 18 hours and then the separated Wittig salt was filtered off, washed with ethyl acetate and dried at 50° C./12 Torr up to constant weight. There were obtained 7.6 g (56%) of (4'-pentyl-4-biphenylyl)methyl-triphenylphosphonium bromide as a colourless powder of melting point 202°-204° C. From the filtrate, concentrated to 50 ml, there could be isolated a further 3.3 g (24%) of the bromide of melting point 202°-204.5° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[N:5][N:4]=[N:3]1.C([Li])CCC.[F:13][C:14]1[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][C:15]=1[C:16]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=1[F:25])=[O:17]>O1CCCC1>[F:13][C:14]1[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][C:15]=1[C:16]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=1[F:25])([OH:17])[CH2:7][C:6]1[N:2]([CH3:1])[N:3]=[N:4][N:5]=1
Reactant: Cc1nnnn1C
Reactant: Cc1ccc(C(=O)c2ccc(C)cc2F)c(F)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(C(O)(Cc2nnnn2C)c2ccc(C)cc2F)c(F)c1
Temperature: -10 °C
Reaction time: 0.17 h

Procedure:
To a solution of 1,5-dimethyltetrazole (4.6 g, 4.7 mmoles) in tetrahydrofuran (40 mL) at -50° C. was added butyl lithium solution (21.4 mL of a 2.2 M solution, 4.7 mmoles). After stirring for 10 minutes, a solution of 2,2'-difluoro-4,4'-dimethylbenzophenone in tetrahydrofuran (15 mL) was added. The solution was stirred for 2.5 hours during which time it was allowed to warm to -10° C. The reaction was quenched by adding 1N hydrochloric acid. The layers were separated and the aqueous layer was extracted with methylene chloride. The combined organic fractions were dried (MgSO4) and evaporated. The residue was triturated with diethyl ether and crystallized from isopropyl acetate to give 8.0 g of the title compound; m.p=150°-151° C. MS: M+ =344.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([O-:10])=O)[CH:5]=[C:4]([Cl:11])[C:3]=1[C:12]([O:14][CH3:15])=[O:13].[C:16]1([C@H:26]([NH2:28])[CH3:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[Cl:11][C:4]1[CH:5]=[C:6]([C:8]([NH:28][C@@H:26]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)[CH3:27])=[O:10])[CH:7]=[C:2]([Cl:1])[C:3]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1c(Cl)cc(C(=O)[O-])cc1Cl
Reactant: C[C@@H](N)c1cccc2ccccc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1c(Cl)cc(C(=O)N[C@H](C)c2cccc3ccccc23)cc1Cl
Yield: 96 %

Procedure:
A solution of 2,6-dichlorobenzene-1,4-dicarboxylic acid, 1-methyl ester (Example 4; 3.00 g, 12.0 mmol), (R)-(+)-1-(1-naphthyl)ethylamine (2.00 g, 11.7 mmol), HBTU (5.68 g, 15.0 mmol), HOBT (2.04 g, 15.1 mmol), and diisopropylethylamine (6.20 g, 48.0 mmol) in N,N-dimethylformamide (50 mL) was stirred at room temperature over the weekend. The solvent was evaporated and ethyl acetate (150 mL) was added. The solution was washed with 1 M HCl (100 mL) and the aqueous layer was back-extracted with ethyl, acetate (100 mL). The combined organic layers were washed with saturated aqueous sodium hydrogen carbonate and brine (200 mL each), then dried (MgSO4), filtered, evaporated and chromatographed (30% ethyl acetate/hexanes) to give 2,6-dichloro-4-[[[(1R)-1-(1-naphthalenyl)ethyl]amino]carbonyl]benzoic acid, methyl ester (4.52 g, 96%) as a white foam.