Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C([O-])=O.[NH4+]>CO.[Pd]>[N:7]1[CH:2]=[CH:3][CH:4]=[C:5]([N:8]2[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:18])[CH3:20])[CH2:10][CH2:9]2)[N:6]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccc(Cl)nn2)CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CCN(c2cccnn2)CC1
Temperature: 0 °C
Yield: 56.1 %

Procedure:
tert-Butyl [1-(6-chloropyridazin-3-yl)piperidin-4-yl]carbamate (0.5 g, 1.60 mmol) was dissolved in MeOH (20 ml) and cooled to 0° C. with an icebath. 10% Pd/C (60 mg) was added carefully. Ammonium formate (0.30 g, 4.80 mmol) was added and the reaction mixture was heated to 40° C. Ammonium formate (0.604 g, 9.59 mmol) was added in portions during the reaction, after 33 h at 40° C. the reaction mixture was filtered through celite and the celite was washed with MeOH (20 ml). The reaction mixture was evaporated and the residue was diluted with EtOAc (100 mL) and washed with water (200 ml). The organic phase was dried (Na2SO4) filtered and evaporated. The residue was purified by silica gel column chromatography using a 98:2 mixture of DCM:MeOH to give the title compound as a solid (0.25 g, 57%). 1H NMR (CDCl3, 500 MHz): δ 8.52-8.47 (m, 1H), 7.17-7.11 (m, 1H), 6.91-6.84 (m, 1H), 4.67-4.57 (m, 1H), 4.30-4.21 (m, 2H), 3.75-3.62 (m, 1H), 3.09-2.99 (m, 2H), 2.05-1.96 (m, 2H), 1.46-1.35 (m, 2H), 1.40 (s, 9H); 13C NMR (CDCl3, 125 MHz): δ 160.0, 155.4, 143.3, 127.5, 112.7, 79.6, 48.2, 44.3, 32.1, 28.6.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:35]=[CH:34][N:33]([C:36]3[N:44]=[CH:43][CH:42]=[CH:41][C:37]=3[C:38]([OH:40])=O)[N:32]=2)=[CH:27][CH:26]=1.[Cl-].[CH2:46]([O:48][C:49](=[O:61])[CH:50]([OH:60])[CH:51]([NH3+:59])[CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[CH3:47]>ClCCl.COC(C)(C)C.CCN(CC)CC>[F:24][C:25]1[CH:26]=[CH:27][C:28]([C:31]2[CH:35]=[CH:34][N:33]([C:36]3[N:44]=[CH:43][CH:42]=[CH:41][C:37]=3[C:38]([NH:59][CH:51]([CH2:52][C:53]3[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=3)[CH:50]([OH:60])[C:49]([O:48][CH2:46][CH3:47])=[O:61])=[O:40])[N:32]=2)=[CH:29][CH:30]=1
Reactant: O=C(O)c1cccnc1-n1ccc(-c2ccc(F)cc2)n1
Reactant: CCOC(=O)C(O)C([NH3+])Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: COC(C)(C)C
Solvent: ClCCl
Product: CCOC(=O)C(O)C(Cc1ccccc1)NC(=O)c1cccnc1-n1ccc(-c2ccc(F)cc2)n1
Temperature: 5 °C
Reaction time: 0.08 h
Yield: 69.4 %

Procedure:
N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC) (4.47 g, 23.3 mmol), 1-hydroxybenzotriazole hydrate (HOBt) (3.57 g, 23.3 mmol) and triethylamine (Et3N) (4.5 ml, 32.3 mmol) were successively added to a solution of 2-(3-(4-fluorophenyl)-1H-pyrazol-1-yl)nicotinic acid (6.0 g, 21.8 mmol) and 4-ethoxy-3-hydroxy-4-oxo-1-phenylbutan-2-aminium chloride (6.60 g, 25.4 mmol) in dichloromethane (300 ml) at 5° C., and the mixture was stirred at 5° C. for about 5 minutes. A pH of 10 was adjusted by adding 6 ml Et3N, the mixture stirred for 1 h at 5° C. and then overnight at room temperature. The mixture then was concentrated under reduced pressure, poured into 1000 ml of water, the precipitate formed was filtered off with suction and dried in vacuo to give 7.8 g, which were treated 100 ml of methyl-tert.butylether to give 7.39 g of the desired product; ESI-MS [M+H]+: 489.2.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([F:12])[CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[CH2:7]2.[C:13](Cl)(=[O:15])[CH3:14]>O1CCCC1>[F:12][C:4]1[CH:5]=[C:6]2[C:10](=[C:2]([NH:1][C:13](=[O:15])[CH3:14])[CH:3]=1)[NH:9][C:8](=[O:11])[CH2:7]2
Reactant: Nc1cc(F)cc2c1NC(=O)C2
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Product: CC(=O)Nc1cc(F)cc2c1NC(=O)C2
Temperature: 0 °C
Yield: 96.1 %

Procedure:
A stirred solution of 7-amino-5-fluoro-1,3-dihydro-indol-2-one (1.0 g, 6 mmol) obtained from Example 4 in 30 ml of tetrahydrofuran was added with tirethylamine (1.3 ml, 9 mmol). The solution was cooled down to 0° C. in an ice-water bath and added with acetyl chloride (1.3 ml, 9 mmol) dropwise. The resulting mixture was heated to reflux for 1.5 hours and cooled until precipitate was formed. The solid was filtered, washed with water (50 ml×3) and dried in vacuo to give N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-7-yl)-acetamide (1.2 g, 96%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[C:7]3[CH:25]=[CH:24][C:23]([C:26]4[CH:27]=[CH:28][C:29]([NH2:32])=[N:30][CH:31]=4)=[CH:22][C:8]=3[N:9]([C:13]3[CH:14]=[N:15][C:16]([N+:19]([O-])=O)=[CH:17][CH:18]=3)[CH2:10][C@@H:11]([CH3:12])[C:5]2=[N:4][N:3]=1.[Cl-].[NH4+]>[Fe].C(O)C>[CH3:1][C:2]1[N:6]2[C:7]3[CH:25]=[CH:24][C:23]([C:26]4[CH:27]=[CH:28][C:29]([NH2:32])=[N:30][CH:31]=4)=[CH:22][C:8]=3[N:9]([C:13]3[CH:18]=[CH:17][C:16]([NH2:19])=[N:15][CH:14]=3)[CH2:10][C@@H:11]([CH3:12])[C:5]2=[N:4][N:3]=1
Reactant: Cc1nnc2n1-c1ccc(-c3ccc(N)nc3)cc1N(c1ccc([N+](=O)[O-])nc1)C[C@H]2C
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: Cc1nnc2n1-c1ccc(-c3ccc(N)nc3)cc1N(c1ccc(N)nc1)C[C@H]2C
Temperature: 60 °C
Yield: 10 %

Procedure:
Iron powder (56 mg, 1 mmol) was added to a mixture of (R)-5-(1,4-dimethyl-6-(6-nitropyridin-3-yl)-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepin-8-yl)pyridin-2-amine (86 mg, 0.2 mmol) in a mixed solvents of ammonium chloride aqueous (2 mL) and ethanol (10 mL). Once addition was complete, the mixture was heated to 60° C. for 2 hours. The mixture was filtered. The filtrate was concentrated, diluted with water (10 mL), extracted with ethyl acetate (20 mL×2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give a residue which was purified by column chromatography (silica gel, dichloromethane/methanol=8:1) to afford (R)-5,5′-(1,4-dimethyl-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepine-6,8(5H)-diyl)dipyridin-2-amine (8 mg, 20%).
Reaction SMILES: [F:1][C:2]1([F:19])[CH2:7][O:6][C:5]([NH2:8])=[N:4][C@@:3]21[C:17]1[C:12](=[CH:13][CH:14]=[C:15]([NH2:18])[CH:16]=1)[O:11][CH2:10][CH2:9]2.Cl[C:21]1[CH:22]=N[NH:24][C:25]=1[C:26]([OH:28])=O>>[NH2:8][C:5]1[O:6][CH2:7][C:2]([F:1])([F:19])[C@@:3]2([C:17]3[C:12](=[CH:13][CH:14]=[C:15]([NH:18][C:26](=[O:28])[C:25]4[CH:21]=[CH:22][C:2]([C:3]#[N:4])=[CH:7][N:24]=4)[CH:16]=3)[O:11][CH2:10][CH2:9]2)[N:4]=1
Reactant: O=C(O)c1[nH]ncc1Cl
Reactant: NC1=N[C@@]2(CCOc3ccc(N)cc32)C(F)(F)CO1
Product: N#Cc1ccc(C(=O)Nc2ccc3c(c2)[C@@]2(CCO3)N=C(N)OCC2(F)F)nc1
Yield: 34 %

Procedure:
The condensation of (R)-5′,5′-difluoro-5′,6′-dihydrospiro[chroman-4,4′-[1,3]oxazine]-2′,6-diamine (intermediate B7.1) and 4-chloro-1H-pyrazole-5-carboxylic acid yielded the title compound (34% yield) as a pale yellow solid. MS (ISP): m/z=398.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:21]O)[CH:5]=[C:6]([Cl:20])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15]C)=[C:11]([CH:17]([CH3:19])[CH3:18])[CH:10]=1.B(Br)(Br)[Br:24]>C(Cl)Cl>[Br:24][CH2:21][C:4]1[CH:3]=[C:2]([Cl:1])[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([CH:17]([CH3:19])[CH3:18])[CH:10]=2)=[C:6]([Cl:20])[CH:5]=1
Reactant: COc1ccc(Oc2c(Cl)cc(CO)cc2Cl)cc1C(C)C
Reactant: BrB(Br)Br
Solvent: ClCCl
Product: CC(C)c1cc(Oc2c(Cl)cc(CBr)cc2Cl)ccc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.7 %

Procedure:
To a solution of the title compound of Step A (75 mg, 0.22 mmol) in dry methylene chloride (2 ml) at room temperature under nitrogen was added boron tribromide (1M in methylene chloride, 0.44 ml, 0.44 mmol). The reaction mixture was stirred at room temperature for about one hour, quenched with water (5 ml) and extracted with methylene chloride (3×5 ml). The combined organic extracts were dried, filtered, and concentrated. The crude product was purified by preparative TLC (methylene chloride) to afford the title compound (59 mg) as an oil. MS (APCI−) Calc: 388.0, found: 386.9 (M−1).
Reaction SMILES: [C:1]([NH:4][C:5]1S[C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=[CH:19][C:7]=2[C:6]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21])(=[O:3])[CH3:2]>[Ni]>[CH2:23]([O:22][C:20](=[O:21])[CH:6]([CH:7]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:8]1)[CH2:5][NH:4][C:1](=[O:3])[CH3:2])[CH3:24]
Reactant: CCOC(=O)c1c(NC(C)=O)sc2c1C=CC=CC=CC=CC=C2
Agent: [Ni]
Product: CCOC(=O)C(CNC(C)=O)C1CCCCCCCCCCC1
Yield: 98.5 %

Procedure:
Ethyl 2-acetamidocyclododeca[b]thiophene-3-carboxylate (2.3366 g, 6.65 mmol) was reductively desulfurized using Raney nickel to yield the title compound as a yellow oil (2.1314 g, 6.55 mmol, 98.5%); TLC: Rf=0.75 (Solvent I), 0.46 (Solvent J); IR (cm−1). 3316 (NH), 2903 (CH aliphatic), 1725 (ester C═O), 1661 (amide C═O); 1H nmr (DMSO-d6): δ 7.88 (br s, 1H), 4.05 (q, 2H, J=8.1 Hz), 3.59 (m, 2H), 2.45 (m, 1H), 1.74 (s, 3H), 1.50 (m, 1H), 1.28 (m, 22H), 1.15 (t, 3H, J=8.1 Hz).
Reaction SMILES: [F:1][C:2]1[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:3]=1[CH2:4][S:5][C:6]1[N:11]=[C:10]([NH:12][S:13]([N:16]2[CH2:22][CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]2)(=[O:15])=[O:14])[CH:9]=[C:8]([O:30][CH3:31])[N:7]=1.C(O)(C(F)(F)F)=O>CO>[F:1][C:2]1[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:3]=1[CH2:4][S:5][C:6]1[N:11]=[C:10]([NH:12][S:13]([N:16]2[CH2:22][CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)(=[O:14])=[O:15])[CH:9]=[C:8]([O:30][CH3:31])[N:7]=1
Reactant: COc1cc(NS(=O)(=O)N2CCCN(C(=O)OC(C)(C)C)CC2)nc(SCc2cccc(F)c2F)n1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(NS(=O)(=O)N2CCCNCC2)nc(SCc2cccc(F)c2F)n1
Reaction time: 0.5 h

Procedure:
A solution of tert-Butyl 4-[({2-[(2,3-difluorobenzyl)thio]-6-methoxypyrimidin-4-yl}amino)sulfonyl]-1,4-diazepane-1-carboxylate (the product of step i, 0.22 g) in 1:1 TFA:methanol (6 ml) was stirred at room temperature for 3 h then the volatiles evaporated and 7M ammonia in methanol (5 ml) added to the residue. The solution was stirred for 30 min then the volatiles evaporated and the resulting solid washed with methanol, DCM, dimethyl sulfoxide and H2O to afford the title compound as a white powder. Yield: δ 1 mg
Reaction SMILES: [N:1]1([S:7]([C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([OH:15])=O)(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:19][C:20]1[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=1[NH2:22]>>[Cl:19][C:20]1[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=1[NH:22][C:13](=[O:15])[C:12]1[CH:16]=[CH:17][CH:18]=[C:10]([S:7]([N:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)(=[O:8])=[O:9])[CH:11]=1
Reactant: Nc1ccccc1Cl
Reactant: O=C(O)c1cccc(S(=O)(=O)N2CCCCC2)c1
Product: O=C(Nc1ccccc1Cl)c1cccc(S(=O)(=O)N2CCCCC2)c1

Procedure:
The entitled compound was produced according to the method of Example 73 but using 3-(piperidin-1-ylsulfonyl)benzoic acid and 2-chloroaniline as the starting materials.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH:10]1([S:16](C2C=CC=CC=2CC2C3C(=CC=C(F)C=3)N(CC(O)=O)C=2C)(=O)=O)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>>[CH:10]1([S:16][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: Cc1c(Cc2ccccc2S(=O)(=O)C2CCCCC2)c2cc(F)ccc2n1CC(=O)O
Reactant: O=Cc1ccc(F)cc1
Product: O=Cc1ccc(SC2CCCCC2)cc1

Procedure:
4-Fluorobenzaldehyde was used as a starting material, otherwise this compound was prepared in a similar manner to Compound 1, following Procedure A.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](B2OC(C)(C)C(C)(C)O2)=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.Br[C:36]1[C:48]([CH3:49])=[CH:47][C:39]([O:40][CH:41]2[CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)=[CH:38][C:37]=1[CH3:50]>>[CH3:50][C:37]1[CH:38]=[C:39]([O:40][CH:41]2[CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)[CH:47]=[C:48]([CH3:49])[C:36]=1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[C:10]2[C:6]=1[CH2:7][CH2:8][C@H:9]2[O:11][C:12]1[CH:25]=[CH:24][C:15]2[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=2[CH:13]=1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Reactant: Cc1cc(OC2CCOCC2)cc(C)c1Br
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(OC6CCOCC6)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate and 4-(4-bromo-3,5-dimethylphenoxy)tetrahydro-2H-pyran following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 4): tR=1.92 min; Mass spectrum (ESI+): m/z=569 [M+Na]+.
Reaction SMILES: [C:1]([C:4]1[C:10]([F:11])=[CH:9][C:7]([NH2:8])=[C:6]([Cl:12])[CH:5]=1)(=[O:3])[CH3:2].[I:13]I>CC(O)=O>[C:1]([C:4]1[C:10]([F:11])=[C:9]([I:13])[C:7]([NH2:8])=[C:6]([Cl:12])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: II
Reactant: CC(=O)c1cc(Cl)c(N)cc1F
Solvent: CC(=O)O
Product: CC(=O)c1cc(Cl)c(N)c(I)c1F
Reaction time: 4 h

Procedure:
In 4.8 mL of HOAc, 0.5 g of 4-acetyl-2-chloro-5-fluoroaniline and 0.47 g of HgO are stirred under N2. At room temperature over 4 hours, 0.79 g of I2 is added and after stirring an additional hour, the mixture is filtered and the filter cake washed with 3 mL of AcOH To the filtrate and washed solution, 75 mL of H2O is added to precipitate the title compound, which is collected, washed with H2O and air dried to afford 0.83 g, m.p. 117°-119° C.
Reaction SMILES: [CH2:1]([N:3]([CH:11]1[CH2:16][CH2:15][CH:14]([O:17][C:18]2[C:29]3[C:28]4[C@@H:27]([CH2:30][CH2:31][OH:32])[CH2:26][CH2:25][C:24]=4[S:23][C:22]=3[N:21]=[CH:20][N:19]=2)[CH2:13][CH2:12]1)[C:4](=[O:10])[O:5][C:6]([CH3:9])([CH3:8])[CH3:7])[CH3:2].C1C=C[NH+]=CC=1.C1C=C[NH+]=CC=1.[O-:45][Cr](O[Cr]([O-])(=O)=O)(=O)=O>CN(C=O)C.O>[C:6]([O:5][C:4]([N:3]([CH2:1][CH3:2])[CH:11]1[CH2:12][CH2:13][CH:14]([O:17][C:18]2[C:29]3[C:28]4[C@@H:27]([CH2:30][C:31]([OH:45])=[O:32])[CH2:26][CH2:25][C:24]=4[S:23][C:22]=3[N:21]=[CH:20][N:19]=2)[CH2:15][CH2:16]1)=[O:10])([CH3:8])([CH3:7])[CH3:9]
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Reactant: CCN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](CCO)CC4)CC1
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Solvent: O
Product: CCN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](CC(=O)O)CC4)CC1
Yield: 67.2 %

Procedure:
A solution of tert-butyl N-ethyl-N-(4-[[(3R)-3-(2-hydroxyethyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)carbamate (450 mg, 0.97 mmol, 1.00 equiv) and PDC (1791 mg, 4.76 mmol, 4.88 equiv) in 5 mL of DMF was stirred for 14 hrs at 25° C. After completion, the resulting solution was diluted with water and extracted with 3×50 mL of ethyl acetate. The combined organic layers were washed with 3×20 mL of brine, dried over sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (2:1) to give 310 mg (67%) of 2-[(3R)-12-[(4-[[(tert-butoxy)carbonyl](ethyl)amino]cyclohexyl)oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]acetic acid as a colorless oil. MS (ES): m/z 476 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[NH:10][C:11]2[C:17]3[CH2:18][C:19]([CH3:22])([CH3:21])[O:20][C:16]=3[C:15]([C:23](O)=[O:24])=[CH:14][C:12]=2[N:13]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.CN(C=O)C.[Cl:53][C:54]1[CH:60]=[CH:59][C:57]([NH2:58])=[CH:56][CH:55]=1>C1COCC1>[Cl:53][C:54]1[CH:60]=[CH:59][C:57]([NH:58][C:23]([C:15]2[C:16]3[O:20][C:19]([CH3:22])([CH3:21])[CH2:18][C:17]=3[C:11]3[NH:10][C:9]([NH:8][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])=[N:13][C:12]=3[CH:14]=2)=[O:24])=[CH:56][CH:55]=1
Reactant: CC1(C)Cc2c(c(C(=O)O)cc3nc(Nc4ccccc4Cl)[nH]c23)O1
Reactant: Nc1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC1(C)Cc2c(c(C(=O)Nc3ccc(Cl)cc3)cc3nc(Nc4ccccc4Cl)[nH]c23)O1
Yield: 23.1 %

Procedure:
The title compound was prepared following the procedure as described for Example-1 using 2-[(2-chlorophenyl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylic acid (Intermediate-12, 0.050 g, 0.139 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (0.089 g, 0.277 mmol), TEA (1.0 mL), DMF (1.0 mL), THF (5.0 mL) and 4-chloro aniline (0.035 g, 0275 mmol) to afford 0.015 g of the desired product. 1HNMR (DMSO-d6): δ 1.60 (s, 6H), 3.17 (s, 2H), 7.05 (t, J=7.5 Hz, 1H), 7.36-7.43 (m, 2H), 7.49 (d, J=7.8 Hz, 2H), 7.75 (d, J=8.1 Hz, 2H), 8.58-8.60 (m, 1H), 9.07 (s, 1H), 9.87 (s, 1H), 11.02 (s, 1H), 11.36 (s, 1H); MS [M+H]+: 467.23.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[CH3:18][O:19][C:20]1[C:21]([C:25](O)=[O:26])=[CH:22][S:23][CH:24]=1>>[CH3:18][O:19][C:20]1[C:21]([C:25]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[O:26])=[CH:22][S:23][CH:24]=1
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: COc1cscc1C(=O)O
Product: COc1cscc1C(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2c1
Yield: 109.2 %

Procedure:
Beginning with 7.0 mg (0.03 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 14.2 mg (0.09 mMol) 4-methoxy-3-thienoic acid, 12.1 mg of the title compound were recovered.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[OH:12].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:13]([O:12][C:3]1[C:2]([F:1])=[C:7]([F:8])[CH:6]=[CH:5][C:4]=1[N+:9]([O-:11])=[O:10])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(F)c(F)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 97 %

Procedure:
A mixture of 2,3-difluoro-6-nitrophenol (15.1 g), benzyl bromide (10.8 mL) and potassium carbonate (11.9 g) in N,N-dimethylformamide (60 mL) was stirred at room temperature for 15 h. The reaction mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and water. The organic layer was washed with successively water and brine, dried (MgSO4), filtered, and concentrated to give the title compound (22.1 g, 97%) as a light yellow solid. MS 264 (MH+).
Reaction SMILES: BrC1C2OCCNC=2C=C(C)C=1.[Br:13][C:14]1[C:24]2[O:23][CH2:22][CH2:21][CH2:20][NH:19][C:18]=2[CH:17]=[CH:16][CH:15]=1.[C:25]1([S:31](Cl)(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:25]1([S:31]([N:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[C:14]([Br:13])[C:24]=3[O:23][CH2:22][CH2:21][CH2:20]2)(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Brc1cccc2c1OCCCN2
Agent: Cc1cc(Br)c2c(c1)NCCO2
Product: O=S(=O)(c1ccccc1)N1CCCOc2c(Br)cccc21

Procedure:
In another variation of the above procedure, 8-bromo-6-methyl-3,4-dihydro-2H-benzo[1,4]oxazine was replaced with 4-bromo-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycloheptene (obtained by reduction of 4-bromo-6,7-dihydro-9H-5-oxa-9-aza-benzocyclohepten-8-one, which in turn was prepared by reaction of 2-amino-6-bromophenol with 3-chloropropionyl chloride as described by Combs et al.; J. Med. Chem.; 33; 380-386 1990). Reaction of 4-bromo-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycloheptene with benzenesulfonyl chloride yielded 9-benzenesulfonyl-4-bromo-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycloheptene as a white solid, MS: M+=336.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([CH3:15])=[CH:10][C:9]=1[NH:16][C:17](=[O:33])[CH2:18][C:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[CH:31]=[N:30][CH:29]=[CH:28][N:27]=2)[CH:21]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:14][C:12]1[C:11]([CH3:15])=[CH:10][C:9]2[NH:16][C:17](=[O:33])[CH2:18][C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4[CH:31]=[N:30][CH:29]=[CH:28][N:27]=4)[CH:21]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: Cc1cc(NC(=O)CC(=O)c2cccc(-c3cnccn3)c2)c(NC(=O)OC(C)(C)C)cc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc2c(cc1Cl)N=C(c1cccc(-c3cnccn3)c1)CC(=O)N2

Procedure:
The title compound was prepared from {5-chloro-4-methyl-2-[3-oxo-3-(3-pyrazin-2-yl-phenyl)-propionylamino]-phenyl}-carbamic acid tert-butyl ester (Example M94) (0.38 g, 0.79 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (240 mg, 84%).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])=[N:4][C:5]([OH:8])=[N:6][CH:7]=1.[N:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[C:19]=[O:20]>C1COCC1>[F:1][C:2]1[C:3]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])=[N:4][C:5](=[O:8])[N:6]([C:19]([NH:18][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:20])[CH:7]=1
Reactant: Oc1ncc(F)c(NCc2ccccc2F)n1
Reactant: O=C=Nc1ccccc1
Solvent: C1CCOC1
Product: O=C(Nc1ccccc1)n1cc(F)c(NCc2ccccc2F)nc1=O
Reaction time: 4.5 h
Yield: 67.5 %

Procedure:
A 25 mL screw-top vial was charged with 5-fluoro-4-(2-fluorobenzylamino)pyrimidin-2-ol (74.3 mg, 0.313 mmol), THF (2 mL), and isocyanatobenzene (0.33 mL, 0.313 mmol). The resulting mixture was then agitated on an orbital shaker for 4.5 h at which time it was concentrated to dryness in vacuo. The dried material was then purified by normal phase chromatography (gradient, EtOAc/Hexane) to provide 5-fluoro-4-(2-fluorobenzylamino)-2-oxo-N-phenylpyrimidine-1(2H)-carboxamide (75.3 mg, 68%) as a white solid: mp 154-157° C.; 1H NMR (400 MHz, CDCl3) δ 12.65 (s, 1H), 8.51 (d, J=7.1 Hz, 1H), 7.63-7.55 (m, 2H), 7.46 (td, J=7.5, 1.7 Hz, 1H), 7.41-7.28 (m, 3H), 7.19-7.05 (m, 3H), 6.03 (s, 1H), 4.86 (d, J=5.9 Hz, 2H); ESIMS m/z 355 ([M−H]−).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:17][C:18]([O:20]CC)=[O:19])[N:5]([CH3:16])[C:6]=1[C:7](=[O:15])[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1>[OH-].[Na+].C(O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([CH2:17][C:18]([OH:20])=[O:19])[N:5]([CH3:16])[C:6]=1[C:7](=[O:15])[C:8]1[CH:9]=[CH:10][C:11]([Cl:14])=[CH:12][CH:13]=1
Reactant: CCOC(=O)Cc1cc(Br)c(C(=O)c2ccc(Cl)cc2)n1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cn1c(CC(=O)O)cc(Br)c1C(=O)c1ccc(Cl)cc1

Procedure:
A suspension of 0.9 g. of ethyl 4-bromo-5-(p-chlorobenzoyl)-1-methylpyrrole-2-acetate in 5 ml of 0.5N sodium hydroxide solution containing a few drops of ethanol is heated under reflux for one hour. At the end of 1 hour it is cooled, diluted with water and filtered, and the filtrate washed with ether. The aqueous filtrate is then acidified with dilute hydrochloric acid and the resulting precipitated solid is collected and air dried. Recrystallization thereof from acetonitrile gives 4-bromo-5-(p-chlorobenzoyl)- 1-methylpyrrole-2-acetic acid as a pink solid; m.p. 190° C. (dec.)