Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][S:15](=[O:18])[CH2:14][CH2:13]2)[C:9]2[C:4](=[N:5][C:6]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[C:7]([Cl:19])[N:8]=2)[N:3]=1.[NH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[Cl:19][C:7]1[N:8]=[C:9]2[C:4](=[N:5][C:6]=1[N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)[N:3]=[C:2]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[N:11]=[C:10]2[N:12]1[CH2:17][CH2:16][S:15](=[O:18])[CH2:14][CH2:13]1
Reactant: C1CNCCN1
Reactant: O=S1CCN(c2nc(Cl)nc3nc(N4CCOCC4)c(Cl)nc23)CC1
Product: O=S1CCN(c2nc(N3CCNCC3)nc3nc(N4CCOCC4)c(Cl)nc23)CC1

Procedure:
This compound was prepared analogous to Example 1 from 2,6-dichloro-7-morpholino-4-(1-oxido-thiomorpholino)pteridine and piperazine.
Reaction SMILES: F[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH2:12]([NH2:14])[CH3:13]>C1COCC1.CCOC(C)=O>[CH2:12]([NH:14][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10])[CH3:13]
Reactant: CCN
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCNc1ccc(N)cc1[N+](=O)[O-]
Temperature: 120 °C
Yield: 98 %

Procedure:
To a pressure tube was added 4-fluoro-3-nitroaniline (550 mg, 3.50 mmol) and a 2.0 M solution of ethylamine in THF (8 mL). The sealed tube was heated at 120° C. for 24 h. The reaction solution was cooled, diluted with EtOAc (30 mL), washed with saturated NaHCO3 (2×25 mL), dried over Na2SO4, and concentrated under reduced pressure to provide the title compound (625 mg, 98%) as a purple solid. 1H-NMR (CDCl3): δ 7.72 (1H, br s), 7.49 (1H, d), 6.96 (1H, dd), 6.74 (1H, d), 3.45 (2H, br s), 3.30 (2H, m), 1.33 (3H, t).
Reaction SMILES: Br.[NH2:2][C:3]1[C:8]([CH2:9]Br)=[CH:7][C:6]([Br:11])=[CH:5][N:4]=1.[CH3:12][NH2:13]>C1COCC1>[NH2:2][C:3]1[C:8]([CH2:9][NH:13][CH3:12])=[CH:7][C:6]([Br:11])=[CH:5][N:4]=1
Reactant: CN
Reactant: Nc1ncc(Br)cc1CBr
Agent: Br
Solvent: C1CCOC1
Product: CNCc1cc(Br)cnc1N
Yield: 80 %

Procedure:
A solution of the 2-amino-3-(bromomethyl)-5-bromopyridine hydrobromide salt (prepared above) in 40% aqueous methylamine (50 mL) and THF (50 mL) was stirred at RT overnight in a pressure bottle. The reaction solution was concentrated and extracted with EtOAc (2×100 mL). The combined organic phases were washed with H2O, dried over Na2SO4 and concentrated. Purification on silica gel afforded the title compound (4.25 g, 80%) as a yellow oil: MS (ES) m/e 217 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([OH:9])=O)=[C:5]([CH3:10])[O:4][N:3]=1.[NH2:11][C:12]1[C:21]2[N:22]=[C:23]([CH2:28][CH2:29][CH2:30][CH3:31])[N:24]([CH2:25][CH2:26][NH2:27])[C:20]=2[C:19]2[N:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N:13]=1>>[NH2:11][C:12]1[C:21]2[N:22]=[C:23]([CH2:28][CH2:29][CH2:30][CH3:31])[N:24]([CH2:25][CH2:26][NH:27][C:7]([C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH3:10])=[O:9])[C:20]=2[C:19]2[N:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N:13]=1
Reactant: CCCCc1nc2c(N)nc3cccnc3c2n1CCN
Reactant: Cc1noc(C)c1C(=O)O
Product: CCCCc1nc2c(N)nc3cccnc3c2n1CCNC(=O)c1c(C)noc1C
Yield: 33.2 %

Procedure:
Using the general method of Example 97 3,5-dimethylisoxazole-4-carboxylic acid (0.25 g, 1.7 mmole) was reacted with 2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethaneamine (0.5 g, 1.7 mmol) to provide 0.23 g of N-[2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]-3,5-dimethyl-4-isoxazolecarboxamide as a white powder, m.p. 188-189° C. Analysis: Calculated for C21H25N7O2: %C, 61.90; %H, 6.18; %N, 24.06. Found: %C, 61.92; %H, 6.15; %N, 24.28. HRMS (EI) calcd for C21H25N7O2 (M+) 407.2069. found 407.2068.
Reaction SMILES: [H-].[Na+].CO[C:5](=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH3:13].[C:15](#[N:17])[CH3:16]>C1(C)C=CC=CC=1>[CH3:13][O:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C:5]([CH2:16][C:15]#[N:17])=[O:14]
Reactant: CC#N
Reactant: COC(=O)c1ccccc1OC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1ccccc1C(=O)CC#N
Temperature: 85 °C
Reaction time: 2 h

Procedure:
Into an agitation apparatus with agitator, dropping funnel, gas inlet tube and reflux cooler, under agitation and introduction of nitrogen, 28.8 g (0.6 mol) sodium hydride (as a 50 wt-% suspension in white oil) suspended in 200 ml absolute toluene and 49.9 g (0.3 mol) 2-methoxybenzoic acid methyl ester were introduced. The mixture was heated to 85° C. Within 2 hr, 24.6 g (0.5 mol) absolute acetonitrile was dropped into the heated mixture. Then the reaction mixture was further agitated for 15 hr at 90° C. The mixture was then cooled to 0° C., 300 ml ice water were added carefully under vigorous agitation, and then agitation was continued for 1 hr at 0° C. Then the aqueous phase was removed and extracted with 100 ml toluene. After cooling to 0° C. the aqueous phase was acidified with dilute hydrochloric acid to pH 1. The precipitated product was washed with ice water and dried. The crude product (44 g) was recrystallized from isopropanol; 37.9 g (72% of the theoretical) 2-methoxybenzoylacetonitrile with m.p. 85°-88° were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C@@:12]3([C@H:18]([C:19]4[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=4)[CH2:17][NH:16][CH2:15]3)[N:11]([CH3:27])[C:10]2=[O:28])[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl[S:30]([C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][CH:41]=1)[C:36]([OH:38])=[O:37])(=[O:32])=[O:31].C(=O)(O)[O-].[Na+]>CC(C)=O.O>[C:23]([C:22]1[CH:21]=[CH:20][C:19]([C@H:18]2[C@:12]3([N:11]([CH3:27])[C:10](=[O:28])[N:9]([C:4]4[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=4)[C:13]3=[O:14])[CH2:15][N:16]([S:30]([C:33]3[CH:34]=[C:35]([CH:39]=[CH:40][CH:41]=3)[C:36]([OH:38])=[O:37])(=[O:32])=[O:31])[CH2:17]2)=[CH:26][CH:25]=1)#[N:24]
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Reactant: CN1C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)[C@]12CNC[C@H]2c1ccc(C#N)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CN1C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)[C@]12CN(S(=O)(=O)c1cccc(C(=O)O)c1)C[C@H]2c1ccc(C#N)cc1
Temperature: 25 °C
Yield: 77 %

Procedure:
To a mixture of 4-[(5S,9R)-3-(3,5-Dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non-9-yl]-benzonitrile (Example 15a) (0.11 g, 0.26 mmol) and (3-(Chlorosulfonyl)benzoic acid (0.058 g, 0.26 mmol) in acetone and water (1:1 mL) was added sodium bicarbonate at room temperature. The reaction mixture was stirred at room temperature for forty minutes, quenched by the slow addition of 1N hydrochloric acid (1 mL) and partitioned between DCM (2×20 mL) and brine (25 mL). The DCM layer was dried over sodium sulfate, concentrated and column purified using silica gel chromatography using DCM and MeOH to yield the titled compound (0.12 g). Retention time: 3.39 min. YMC S5 Combiscreen ODS 4.6×50 mm (4 minute gradient). Solvent A=10% MeOH, 90% water and 0.2% phosphoric acid. Solvent B=90% MeOH, 10% water and 0.2% phosphoric acid.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.Cl.[CH3:42][O:43][C:44](=[O:56])[C@@H:45]([NH:48][C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:46][NH2:47]>C(Cl)Cl>[CH3:42][O:43][C:44](=[O:56])[C@@H:45]([NH:48][C:49]([O:51][C:52]([CH3:54])([CH3:53])[CH3:55])=[O:50])[CH2:46][NH:47][C:7]([C:5]1[S:6][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:9]
Reactant: COC(=O)[C@H](CN)NC(=O)OC(C)(C)C
Reactant: O=C(O)c1ccc(Cl)s1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@H](CNC(=O)c1ccc(Cl)s1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Chloro-thiophene-2-carboxylic acid (16.26 g, 0.1 mol) in 500 ml DCM was stirred with DIPEA (51.04 ml, 0.3 mol) and TOTU (32.8 g, 0.1 mmol) at RT for 5 min. Commercially available (S)-3-amino-2-tert-butoxycarbonylamino-propionic acid methyl ester hydrochloride (25.4 g, 0.1 mol) were added and the reaction mixture was stirred at RT overnight and then evaporated. The resulting solid was suspended in 400 ml DCM and washed subsequently with sat. aq NaHCO3, 1N HCl and brine. The organic layer was dried with MgSO4, filtered and evaporated. The crude material was triturated with DCM and the solid filtered off. One obtained 18.4 g white, amorphous solid which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH:15]=[C:14](C=O)[N:13]=[CH:12]1.[CH:18](OC)([O:21][CH3:22])[O:19][CH3:20].C(=O)([O-])[O-].[Na+].[Na+]>CO.O.S([O-])(O)(=O)=O.[Na+]>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH:15]=[C:14]([CH:18]([O:21][CH3:22])[O:19][CH3:20])[N:13]=[CH:12]1
Reactant: COC(OC)OC
Reactant: O=Cc1cn(-c2ccc([N+](=O)[O-])cc2F)cn1
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(OC)c1cn(-c2ccc([N+](=O)[O-])cc2F)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
1-(2-Fluoro-4-nitrophenyl)-1H-imidazole-4-carboxaldehyde (Intermediate 30) (361.7 g, 1.538 mol) was suspended in dry methanol (1700 ml). Trimethyl orthoformate (340 g, 2 mol) and sodium hydrogen sulfate (8 g) were added and the mixture was heated to reflux for 3.5 hours. It was cooled to room temperature, a solution of sodium carbonate in water (10%, 200 ml) was added and it was stirred for 1 hour. It was diluted with water (4 L) and left for 2 hours. The precipitate was collected by filtration, washed with water and dried to give the title compound (402.4 g) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10]([NH2:26])=[N:11][C:12](=[O:25])[CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20](OC)[CH:21]=3)[NH:16][CH:15]=2)[CH:5]=[C:4]([Cl:27])[C:3]=1[NH:28]C(=O)C.[F:32][C:33]1[CH:52]=[CH:51][C:36]([CH2:37]N2C3C(=CC=CC=3)C(CC(O)=O)=C2)=[CH:35][CH:34]=1.ClC1C=C(C=C(Cl)C=1N)CN>>[NH2:28][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([CH2:8][NH:9][C:10]([NH2:26])=[N:11][C:12](=[O:25])[CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH2:37][C:36]3[CH:51]=[CH:52][C:33]([F:32])=[CH:34][CH:35]=3)[CH:15]=2)=[CH:5][C:4]=1[Cl:27]
Reactant: O=C(O)Cc1cn(Cc2ccc(F)cc2)c2ccccc12
Reactant: COc1ccc2[nH]cc(CC(=O)N=C(N)NCc3cc(Cl)c(NC(C)=O)c(Cl)c3)c2c1
Agent: NCc1cc(Cl)c(N)c(Cl)c1
Product: NC(=NC(=O)Cc1cn(Cc2ccc(F)cc2)c2ccccc12)NCc1cc(Cl)c(N)c(Cl)c1

Procedure:
In a manner similar to that used in the preparation of the compound of example 2, but using 2-(1-(4-fluorobenzyl)-1H-indol-3-yl)acetic acid in step 6 (A) and 3,5-dichloro-4-aminobenzylamine (preparation A) in step 6 (B), the title compound was prepared. MS (ESI) (M+H)+=498.08 1H-NMR(500 MHz, CD3OD) δ 7.58 (d, J=7.63 Hz, 1 H), 7.26-7.40 (m, 2 H), 7.13-7.25 (m, 5 H), 7.05-7.13 (m, 1 H), 7.01 (t, J=8.70 Hz, 2 H), 5.33 (s, 2 H), 4.32 (s, 2 H), 3.96 (s, 2 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([S:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]([OH:12])=O)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:32][NH:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([O:41][CH3:42])[CH:36]=1>ClCCl>[CH3:42][O:41][C:37]1[CH:36]=[C:35]([CH:40]=[CH:39][CH:38]=1)[CH2:34][N:33]([CH3:32])[C:10](=[O:12])[CH:9]([C:4]1[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=1)[S:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)C(Sc1ccccc1)c1cc(Cl)cc(Cl)c1
Reactant: CNCc1cccc(OC)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: COc1cccc(CN(C)C(=O)C(Sc2ccccc2)c2cc(Cl)cc(Cl)c2)c1
Reaction time: 1 h
Yield: 76.5 %

Procedure:
A solution of 2-(3,5-dichlorophenyl)-2-(phenyl-sulfanyl)acetic acid (1.65 g) in dichloromethane (50 ml) was treated with 1,1′-carbonyldiimidazole (0.90 g) at room temperature for 2 hours. A solution of N-methyl-3-methoxy-benzylamine (1.0 g) in dichloromethane (15 ml) was added and the stirring was continued for one hour. The reaction mixture was washed with aqueous hydrochloric acid (1M, 50 ml) and aqueous sodium hydroxide (1M, 50 ml). The organic phase was dried and concentrated to dryness leaving crude N-(3-methoxy-benzyl)-N-methyl-2-(3,5-dichlorophenyl)-2-(phenylsulfanyl)-acetamide (1.8 g) as a viscous oil.
Reaction SMILES: [CH2:1]([CH:8]1[C:14]2[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:13]=2[CH2:12][CH2:11][C:10](=O)[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O>O1CCCC1>[CH2:1]([CH:8]1[C:14]2[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:13]=2[CH2:12][CH2:11][CH2:10][NH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2c(c1)C(Cc1ccccc1)NC(=O)CC2
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2c(c1)C(Cc1ccccc1)NCCC2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 68.8 %

Procedure:
To a solution of 2.17 mmol of 1-benzyl-8-methoxy-4,5-dihydro-1H-benzo[c]azepin-3(2H)-one in tetrahydrofuran under nitrogen atmosphere was added 3.25 mmol of lithiumaluminumhydride as 1 M solution in tetrahydrofuran. The solution was heated to reflux and stirred for 1.5 h. The mixture was cooled to room temperature and water (1 ml) was carefully added. The mixture was concentrated and the residue was dissolved in ethyl acetate. The organic phase was extracted with acidified water (acidified with 1 M HCl, 4×). To the combined aqueous phase was added NaOH (50%) until basic and ethyl acetate. The suspension was filtered over celite. The residue was washed with water and ethyl acetate. Phases were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over MgSO4 and filtered. Evaporation of the solvent gave 439 mg of crude material that was purified by flash chromatography to yield 399 mg of 1-benzyl-8-methoxy-2,3,4,5-tetrahydro-1H-benzo[c]azepine (69%).
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.Cl.NC[C:16]([NH:18][C@@H:19]1[CH2:38][CH2:37][C@@:36]2([CH3:39])[C@@H:21]([CH2:22][CH2:23][C@@H:24]3[C@@H:35]2[CH2:34][CH2:33][C@@:32]2([CH3:40])[C@H:25]3[CH2:26][CH2:27][C@@H:28]2[CH:29]([OH:31])[CH3:30])[CH2:20]1)=[O:17].[NH2:41][C@@H:42]1CC[C@@]2(C)[C@@H:44]([CH2:45][CH2:46][C@@H]3[C@@H]2CC[C@@]2(C)[C@H]3CC[C@@H]2C(O)C)[CH2:43]1.C(O)(=O)C1C=CC=NC=1>N1C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:30][C@H:29]([OH:31])[C@@H:28]1[C@:32]2([CH3:40])[C@H:25]([C@H:24]3[C@H:35]([CH2:34][CH2:33]2)[C@:36]2([CH3:39])[C@H:21]([CH2:20][C@H:19]([NH:18][C:16]([C:45]4[CH:46]=[N:41][CH:42]=[CH:43][CH:44]=4)=[O:17])[CH2:38][CH2:37]2)[CH2:22][CH2:23]3)[CH2:26][CH2:27]1
Reactant: CC(O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](NC(=O)CN)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](N)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C(O)c1cccnc1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: C[C@H](O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](NC(=O)c5cccnc5)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 16 h

Procedure:
582 mg of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride were added under an inert atmosphere to a solution of 960 mg of (20S) 3α-amino-5α-pregnane-20-ol, 813 mg of nicotinic acid, 30 ml of chloroform and 6 ml of pyridine and after 31/2 hours, another 291 mg of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride were added to the mixture. The mixture was stirred for 16 hours and was evaporated to dryness. The residue was taken up in 30 ml of water and the solution was iced and vacuum filtered. The product was washed with water, dried at 80° C. under reduced pressure and was crystallized from methanol to obtain 920 mg of N-[(20S) 5α-pregnan-20-ol-3α-yl]-3-pyridinecarboxamide melting at 258° C. and having a specific rotation of [α]D20 =+14.5± 1° (c=1% in pyridine).
Reaction SMILES: [ClH:1].[NH2:2][C:3]1([C:14]([OH:16])=[O:15])[C:11]2[C:6](=[C:7]([F:13])[CH:8]=[C:9]([F:12])[CH:10]=2)[CH2:5][CH2:4]1.Cl.[CH3:18]O>>[ClH:1].[NH2:2][C:3]1([C:14]([O:16][CH3:18])=[O:15])[C:11]2[C:6](=[C:7]([F:13])[CH:8]=[C:9]([F:12])[CH:10]=2)[CH2:5][CH2:4]1
Reactant: NC1(C(=O)O)CCc2c(F)cc(F)cc21
Reactant: CO
Agent: Cl
Product: COC(=O)C1(N)CCc2c(F)cc(F)cc21

Procedure:
A solution of 1-amino-4,6-difluoroindane-1-carboxylic acid hydrochloride (2.00 g, 15.5 mmol) in MeOH (100 mL) was saturated with HCl (g). The resulting mixture was heated at reflux for 20 h and concentrated in vacuo to provide the title compound. MS: m/z=228 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][C:12]([NH:14][C@H:15]2[CH2:20][C:19]3[CH:21]=[CH:22][CH:23]=[C:24]([C:25]([OH:27])=[O:26])[C:18]=3[O:17][B:16]2[OH:28])=[O:13])[CH2:7][CH2:6]1.C(O)(=O)C.[CH3:33][C:34]([CH3:36])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[OH:28][B:16]1[C@@H:15]([NH:14][C:12](=[O:13])[CH2:11][C@H:8]2[CH2:9][CH2:10][C@H:5]([NH:4][CH2:3][CH2:2][NH:1][CH:34]([CH3:36])[CH3:33])[CH2:6][CH2:7]2)[CH2:20][C:19]2[CH:21]=[CH:22][CH:23]=[C:24]([C:25]([OH:27])=[O:26])[C:18]=2[O:17]1
Reactant: CC(C)=O
Reactant: NCCN[C@H]1CC[C@H](CC(=O)N[C@H]2Cc3cccc(C(=O)O)c3OB2O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)NCCN[C@H]1CC[C@H](CC(=O)N[C@H]2Cc3cccc(C(=O)O)c3OB2O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid from Example 15 (92 mg) in MeOH (2 mL) was added TEA (70 μL), acetic acid (30 μL), acetone (0.1 mL) and sodium triacetoxyborohydride (212 mg). The reaction mixture was stirred overnight at RT. Solvent was removed and the product was purified using reverse phase HPLC to afford the titled compound. ESI-MS m/z 432 (MH)+.
Reaction SMILES: C(O)(=O)C.C(OC([NH:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[C:17]([CH3:22])[CH:16]=1)=O)(C)(C)C>ClCCl>[Br:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]([NH:13][NH2:12])=[O:23])=[CH:16][C:17]=1[CH3:22]
Reactant: Cc1cc(C(=O)NNC(=O)OC(C)(C)C)ccc1Br
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1cc(C(=O)NN)ccc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.3 %

Procedure:
500 mL trifluor acetic acid was added to 70 g N′-(4-bromo-3-methyl-benzoyl)-hydrazinecarboxylic acid tert-butyl ester in 1 L dichlormethane. The reaction was stirred 1 h at RT and evaporated. The residue was basicfied with 1N sodiumhydroxide and extracted with saturated sodiumchloride solution and tetrahyrofuran. The organic layer was evaporated and the residue crystallized with ethyl acetate to give 25 g desired product.
Reaction SMILES: F[C:2]1[C:10]([F:11])=[C:9]([F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:13][C:14]1[CH:20]=[C:19]([C:21]#[C:22][CH2:23][O:24][CH3:25])[CH:18]=[CH:17][C:15]=1[NH2:16].[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[F:11][C:10]1[C:2]([NH:16][C:15]2[CH:17]=[CH:18][C:19]([C:21]#[C:22][CH2:23][O:24][CH3:25])=[CH:20][C:14]=2[F:13])=[C:3]([CH:7]=[CH:8][C:9]=1[F:12])[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1ccc(F)c(F)c1F
Reactant: COCC#Cc1ccc(N)c(F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COCC#Cc1ccc(Nc2c(C(=O)O)ccc(F)c2F)c(F)c1

Procedure:
2,3,4-Trifluorobenzoic acid and the product of Example 25, Step A, 2-fluoro-4-(3-methoxy-1-propynyl)aniline, were reacted in the presence of LiHMDS solution in THF by the general procedure of Example 1, Step B. After workup, followed by purification by chromatography on silica gel (10% EtOAc/hexanes as eluant), 3,4-difluoro-2-[[2-fluoro-4-(3-methoxy-1-propynyl)phenyl]amino]-benzoic acid was isolated (62%) as a pale yellow solid; m.p. (EtOAc/hexanes) 221-223° C. 1H NMR [400 MHz, (CD3)2SO] δ 13.60 (br s, 1 H), 9.27 (br s, 1 H), 7.85-7.79 (m, 1H,), 7.36 (dd, J=12.0, 1.8 Hz, 1 H), 7.20 (dd, J=8.3, 1.5 Hz, 1 H), 7.18-7.11 (m, 1 H), 6.96 (td, 8.8, 5.5 Hz, 1 H), 4.31 (s, 2 H), 3.32 (s, 3H ). Anal. Calcd for C17H12F3NO3: C, 60.9; H, 3.6; N, 4.2. Found: C, 61.4; H, 3.6; N, 4.2. Step C: Preparation of 3,4-difluoro-2-[[2-fluoro-4-(3-methoxypropyl)phenyl]-amino]benzoic acid
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH2:10][CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.[CH2:17]([N:19]=[C:20]=[O:21])[CH3:18].O>ClCCl>[CH2:17]([NH:19][C:20]([N:14]1[CH2:13][CH2:12][CH:11]([CH2:10][C:3]2[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=2[F:1])[CH2:16][CH2:15]1)=[O:21])[CH3:18]
Reactant: COc1ccc(F)c(CC2CCNCC2)c1
Reactant: CCN=C=O
Solvent: ClCCl
Solvent: O
Product: CCNC(=O)N1CCC(Cc2cc(OC)ccc2F)CC1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 91.5 %

Procedure:
A magnetically stirred solution of 4-[(2-fluoro-5-methoxyphenyl)methyl]piperidine (0.895 g, 4.01 mmol) in anhydrous dichloromethane (15 mL) at 5° C. was treated dropwise with a solution of ethyl isocyanate (0.320 g, 4.41 mmol) in dry dichloromethane (5 mL). The solution was stirred 0.5 h at 5° C., allowed to warm to room temperature and stirred for 48 h. The solution was poured over ice (50g), and treated with water (200 mL) and dichloromethane (250 mL). The layers were separated, the aqueous phase was back-extracted with fresh dichloromethane (3×200 mL), and the combined organic portions were washed with 1N hydrochloric acid solution (350 mL), 5% sodium hydroxide solution (400 mL), water (400 mL), saturated brine (400 mL), dried is (K2CO3), filtered, and concentrated in vacuo. Drying (85° C.) in vacuo gave 1.08 g (92%) of the desired product as a clear oil: IR (film) 3346, 2930, 1622, 1592, 1538, 1498, 1274, 1252; 1214, 1036 cm-1 ; 1H NMR (CDCl3) δ6.90 (t, J=9.0 Hz, 1H), 6.69-6.60 (m, 2H), 4.50 (bt, J=4.7 Hz, 1H), 3.89 (bd, J=13.2 Hz, 2H), 3.74 (s, 3H), 3.27-3.17 (m, 2H), 2.67 (td, J=12.8, 2.4 Hz, 2H), 2.52 (dd, J=7.1, 1.1 Hz, 2H), 1.74-1.61 (m, 1H), 1.62 (bd, J=13.5 Hz, 2H), 1.18 (qd, J=12.0, 4.0 Hz, 2H), 1.10 (t, J=7.2 Hz, 3H); 13C NMR (CDCl3)δ57.7, 155.7 (d, J=237.1 Hz), 155.4 (d, J=1.7 Hz, 127.8 (d, J=18.0 Hz), 116.6 (d, J=5.1 Hz), 115.5 (d, J=24.7 Hz), 112.1 (d, J=8.0 Hz), 55.7, 44.1, 37.0, 36.2, 35.7, 31.7, 15.6; MS m/z 295 (M+ +1, free base).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:15])=[O:13])=[CH:8][CH:7]=1.[C:25]([C:27]1[CH:28]=[C:29]([CH:44]=[CH:45][CH:46]=1)[O:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([O:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:32]=1)#[CH:26].C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CCCCCC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[O:37]([C:33]1[CH:32]=[C:31]([CH:36]=[CH:35][CH:34]=1)[O:30][C:29]1[CH:28]=[C:27]([C:25]#[C:26][C:2]2[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=2)[O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]([C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:15])=[O:13])=[CH:8][CH:7]=2)[CH:46]=[CH:45][CH:44]=1)[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: O=C(C(=O)c1ccc(Oc2cccc(Br)c2)cc1)c1ccccc1
Reactant: C#Cc1cccc(Oc2cccc(Oc3ccccc3)c2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: O=C(C(=O)c1ccc(Oc2cccc(C#Cc3cccc(Oc4cccc(Oc5ccccc5)c4)c3)c2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 44.1 %

Procedure:
To a 250 ml flask fitted with a reflux condenser, nitrogen inlet and thermometer were added 4(3-bromophenoxy)benzil (11.08 g, 29.08 mmol), 1-(3-ethynylphenoxy)-3-phenoxybenzene (21.64 g, 75.66 mmol), triethylamine (150 ml), and triphenylphosphine (0.40 g). After stirring at room temperature under a nitrogen atmosphere for 10 minutes, cuprous iodide (Alfa 98%, 0.20 g) and dichlorobis(triphenylphosphine)palladium (II) (0.20 g) were added. The flask was heated to an internal temperature of 90° C. and maintained by oil bath heating under nitrogen until TLC indicated reaction completion (4 hr). The triethylamine was distilled from the residue and the residue was suspended in toluene. The toluene was washed with 15% HCl (560 ml) twice and separated. The organic layer was washed with ethylenediamine (20 ml) by adding the ethylenediamine at room temperature, heating to 60° C. for 0.5 h and cooling. Water (250 ml) was added and the toluene was separated from the aqueous layer. The ethylenediamine wash was repeated once more. After washing with water (3×500 ml), the organic layer was dried over anhydrous magnesium sulfate (3.00 g) and the toluene distilled by rotary evaporation at reduced pressure to give a dark brown oil. The oil was dissolved in 4:1 hexane:methylene chloride and chromatographed on a silica gel column (Woelm DCC, 230 g, 5 cm dia×25 cm H) using 4:1 hexane:methylene chloride as the eluent. The product was dried in a 70° C. oven under reduced pressure to afford a light brown tacky oil (7.52 g, 44%).