Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:8]=[C:9]=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:11]1([C:17]2[N:21]([C:22]3[CH:27]=[CH:26][C:25]([S:28]([NH2:31])(=[O:30])=[O:29])=[CH:24][CH:23]=3)[N:20]=[C:19](NC(NC3C=CC=C(C(F)(F)F)C=3)=O)[CH:18]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH:1]1([NH:8][C:9](=[O:10])[NH:8][CH2:1][CH2:2][CH2:3][C:19]2[CH:18]=[C:17]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:21]([C:22]3[CH:23]=[CH:24][C:25]([S:28]([NH2:31])(=[O:30])=[O:29])=[CH:26][CH:27]=3)[N:20]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C=NC1CCCCCC1
Reactant: NS(=O)(=O)c1ccc(-n2nc(NC(=O)Nc3cccc(C(F)(F)F)c3)cc2-c2ccccc2)cc1
Product: NS(=O)(=O)c1ccc(-n2nc(CCCNC(=O)NC3CCCCCC3)cc2-c2ccccc2)cc1
Yield: 91 %

Procedure:
The titled compound was prepared in 91% yield from cycloheptyl isocyanate using the procedure detailed for compound 7. mp 164.2-169.8° C. 1H NMR (300 MHz, DMSO-d6): δ 7.79 (d, J=9 Hz, 2H), 7.47-7.36 (m, 7H), 7.29-7.22 (m, 2H), 6.55 (s, 1H), 5.82-5.70 (m, 2H), 3.63-3.49 (m, 1H), 3.13-3.02 (m, 2H), 2.63 (t, J=8 Hz, 2H), 1.84-1.66 (m, 4H), 1.60-1.27 (m, 10H). MS (ESI) m/z: 496.24 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:21]([C:22]([OH:24])=[O:23])=[C:20]3[C:15]([CH:16]4[CH2:25][CH:17]4[CH2:18][O:19]3)=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[C:4]([CH:26]=[CH2:27])[CH:3]=1.[NH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1>>[N:28]1([CH2:27][CH2:26][C:4]2[CH:3]=[C:2]([F:1])[CH:7]=[CH:6][C:5]=2[S:8]([NH:11][C:12]2[C:21]([C:22]([OH:24])=[O:23])=[C:20]3[C:15]([CH:16]4[CH2:25][CH:17]4[CH2:18][O:19]3)=[CH:14][CH:13]=2)(=[O:9])=[O:10])[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: C1CCNC1
Reactant: C=Cc1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)O)OCC1CC21
Product: O=C(O)c1c(NS(=O)(=O)c2ccc(F)cc2CCN2CCCC2)ccc2c1OCC1CC21

Procedure:
Prepared by proceeding in a similar manner to Example 39, starting from (1aRS,7bSR)-5-(4-fluoro-2-vinylbenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid (Intermediate 74) and pyrrolidine as a white solid.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[N:10]=[C:11]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:20]=3)[C:12]([C:15]([NH2:17])=[O:16])=[N:13][CH:14]=2)[CH2:4][CH2:3]1.C(Cl)(Cl)Cl.[I:33]N1C(=O)CCC1=O>C(#N)C>[OH:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([NH:8][C:9]2[N:10]=[C:11]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([S:25]([CH3:28])(=[O:26])=[O:27])[CH:20]=3)[C:12]([C:15]([NH2:17])=[O:16])=[N:13][C:14]=2[I:33])[CH2:6][CH2:7]1
Reactant: CS(=O)(=O)c1cccc(Nc2nc(N[C@H]3CC[C@H](O)CC3)cnc2C(N)=O)c1
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)c1cccc(Nc2nc(N[C@H]3CC[C@H](O)CC3)c(I)nc2C(N)=O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 5-[(trans-4-hydroxycyclohexyl)amino]-3-{[3-(methylsulfonyl)phenyl]amino}pyrazine-2-carboxamide (Example 111) (150 mg), chloroform (40 mL) and acetonitrile (20 mL), N-iodosuccinimide (87 mg) was added and stirred at room temperature for 2 hours. To the reaction liquid, silica gel was added, and the solvent was distilled off, followed by purification by silica gel column chromatography (eluent; chloroform:methanol=10:0 to 10:1). The resulting crude product was solidified with ethyl acetate and washed with ethyl acetate to give 5-[(trans-4-hydroxycyclohexyl)amino]-6-iodo-3-{[3-(methylsulfonyl)phenyl]amino}pyrazine-2-carboxamide (153 mg) as a light yellow solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[N:8]=2)[CH2:2]1.[Cl:16][C:17]1[CH:22]=[C:21]([N:23]=[C:24]=[O:25])[CH:20]=[CH:19][C:18]=1[CH3:26]>ClCCl>[NH:11]1[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[N:8]=[C:7]1[CH:3]1[CH2:4][CH2:5][CH2:6][N:1]([C:24]([NH:23][C:21]2[CH:20]=[CH:19][C:18]([CH3:26])=[C:17]([Cl:16])[CH:22]=2)=[O:25])[CH2:2]1
Reactant: c1ccc2[nH]c(C3CCCNC3)nc2c1
Reactant: Cc1ccc(N=C=O)cc1Cl
Solvent: ClCCl
Product: Cc1ccc(NC(=O)N2CCCC(c3nc4ccccc4[nH]3)C2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.5 %

Procedure:
2-(piperidin-3-yl)-1H-benzo[d]imidazole (100.0 mg, 0.497 mmol) was dissolved in dichloromethane (3.0 mL). To the stirred suspension was added 2-chloro-4-isocyanato-1-methylbenzene (84.1 mg, 0.502 mmol). The reaction was stirred at ambient temperature for one hour. The crude mixture was then concentrated in vacuo and the residue was dissolved in minimal amounts of dimethylformamide and purified via preparative HPLC (10%-50% acetonitrile in water). The pure fractions were combines and lyophilized to yield the title compound 1 as a fluffy white solid (147.5 mg, 63.7%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.55-1.65 (m, 1H), 1.83 (d, J=13.73 Hz, 1H), 1.97 (q, 0.1=18.28 Hz, 1H), 2.25 (s, 3H), 2.30 (s, 1H), 2.99 (t, J=11.44 Hz, 1H), 3.23 (t, J=13.34 Hz, 1H), 3.34-3.38 (m, 1H), 4.11 (d, J=13.35 Hz, 1H), 4.48 (d, J=13.35 Hz, 1H), 7.20 (d, J=8.4 Hz, 1H), 7.32 (d, J=8.5 Hz, 1H), 7.51-7.34 (m, 1H), 7.63 (s, 1H), 7.78-7.80 (m, 1H), 8.76 (s, 1H), ESI-MS: m/z 369.2 (M+H)+.
Reaction SMILES: [C:1]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:5])[CH2:2][CH2:3][CH3:4].C([O-])(=O)C.[Na+].C(O)C.[F:20][C:21]([F:25])([F:24])[C:22]#[N:23]>O>[C:1]([C:6](=[C:22]([NH2:23])[C:21]([F:25])([F:24])[F:20])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)CC(=O)OCC
Reactant: N#CC(F)(F)F
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCC(=O)C(C(=O)OCC)=C(N)C(F)(F)F
Temperature: 0 °C
Yield: 56.8 %

Procedure:
To a mechanically stirred mixture of 100 g (0.632 mol) of ethyl butyrylacetate, 52 g of sodium acetate, 100 ml of ethanol and 100 ml of water at 70° C. was passed 63 g of trifluoroacetonitrile in 1 day. The reaction mixture was poured into ice water. The oil precipitate was extracted into ether. The ether solution was dried and concentrated. The residue was kugelrohr distilled at 133 Pa (pot temperature 70°-110° C.). The distillate was further distilled through a Vigreaux column at 106 Pa to give 90.9 g (36.3%) of product, bp 90°-97° C., nD25 1.4585.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22]([C:26](O)=[O:27])=[CH:21][CH:20]=[CH:19]2.[NH2:29][CH2:30][C:31]1[CH:47]=[CH:46][C:34]([C:35]([NH:37][C:38]2[CH:43]=[CH:42][C:41]([F:44])=[CH:40][C:39]=2[NH2:45])=[O:36])=[CH:33][CH:32]=1>>[NH2:45][C:39]1[CH:40]=[C:41]([F:44])[CH:42]=[CH:43][C:38]=1[NH:37][C:35]([C:34]1[CH:33]=[CH:32][C:31]([CH2:30][NH:29][C:26]([C:22]2[C:23]3[C:18](=[CH:17][C:16]([O:15][C:6]4[C:5]5[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=5)[N:9]=[CH:8][N:7]=4)=[CH:25][CH:24]=3)[CH:19]=[CH:20][CH:21]=2)=[O:27])=[CH:47][CH:46]=1)=[O:36]
Reactant: NCc1ccc(C(=O)Nc2ccc(F)cc2N)cc1
Reactant: COc1cc2ncnc(Oc3ccc4c(C(=O)O)cccc4c3)c2cc1OC
Product: COc1cc2ncnc(Oc3ccc4c(C(=O)NCc5ccc(C(=O)Nc6ccc(F)cc6N)cc5)cccc4c3)c2cc1OC
Yield: 75 %

Procedure:
The title compound (46.3 mg, 75% yield) was prepared as a brown solid from 6-(6,7-dimethoxyquinazolin-4-yloxy)-1-naphthoic acid (37.6 mg, 0.1 mmol) and 4-(aminomethyl)-N-(2-amino-4-fluorophenyl)benzamide (31.1 mg, 0.12 mmol) by an analogous procedure to that described in example 16. LC-MS (m/z) 618 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C:5](=[CH:6][CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:22]([OH:24])=O)[CH:4]=1)#[N:2].[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([NH2:36])([CH3:35])[CH3:34])=[CH:29][CH:28]=1>>[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([NH:36][C:22]([C@H:12]2[CH2:11][CH2:10][C@H:9]3[C@H:8]4[C@H:17]([CH2:16][CH2:15][C@:13]23[CH3:14])[C@:18]2([CH3:21])[C:5]([CH:4]=[C:3]([C:1]#[N:2])[CH2:20][CH2:19]2)=[CH:6][CH2:7]4)=[O:24])([CH3:34])[CH3:35])=[CH:29][CH:28]=1
Reactant: COc1ccc(C(C)(C)N)cc1
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4C=C(C#N)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)O
Product: COc1ccc(C(C)(C)NC(=O)[C@H]2CC[C@H]3[C@@H]4CC=C5C=C(C#N)CC[C@]5(C)[C@H]4CC[C@]23C)cc1
Yield: 93 %

Procedure:
Following a procedure similar to that described in Preparation 16a, but using 3-cyanoandrosta-3,5-diene-17β-carboxylic acid [prepared as described in Example 1(b)] and 1-(4-methoxyphenyl)-1-methylethylamine as starting materials, in relative proportions similar to those used in that Preparation, the title compound was obtained in a yield of 93%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2OC(C)(C)C(C)(C)O2)[C:5](F)=[N:6][CH:7]=1.C(N(CC)C(C)C)(C)C.[NH2:27][NH2:28].[OH-].[Na+]>C(O)(C)C.C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]2[CH:9]=[N:28][NH:27][C:5]2=[N:6][CH:7]=1
Reactant: CC1(C)OC(c2cc(Cl)cnc2F)OC1(C)C
Reactant: NN
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Clc1cnc2[nH]ncc2c1
Temperature: 65 °C
Yield: 72 %

Procedure:
To a solution of 5-chloro-2-fluoro-3-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)pyridine, 28, (14.5 g, 55.8 mmol) and N,N-diisopropylethylamine (19.5 mL, 112.0 mmol) in isopropanol (200 mL) was added hydrazine (12.0 mL, 382.3 mmol). The mixture was heated to 65° C. overnight. LC-MS indicates desired hydrazine compound formed and the mixture was concentrated in vacuo. The crude residue was taken up in 300 mL of water and 120 mL of EtOH followed by 50 mL of 6N HCl. The resulting mixture was warmed to 45° C. overnight. Once LC-MS indicated completion of the reaction, the mixture was neutralized with 6N NaOH and the pH adjusted to 8. The mixture was concentrated in vacuo to remove volatile EtOH and extracted with EtOAc (3×). The combined organic layer was dried over Na2SO4, filtered through a plug of silica and concentrated in vacuo. Trituration with 10% aqueous acetonitrile provided the desired product (6.15 g, 72% yield, 90% purity by NMR): 1H NMR (300.0 MHz, CDCl3) δ 11.43 (s, 1H), 8.55 (d, J=2.2 Hz, 1H), 8.10 (d, J=2.2 Hz, 1H) and 8.08 (s, 1H) ppm; LC/MS Gradient 10-90%, 0.1% formic 5 min, C18/ACN, RT=2.05 min (M+H) 153.91.
Reaction SMILES: Br[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[N:16]1([C:22]2[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[CH:24][CH:23]=2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:28]([C:25]1[CH:24]=[CH:23][C:22]([N:16]2[CH2:17][CH2:18][N:19]([CH2:2][C:3]([N:5]3[CH2:10][CH2:9][N:8]([CH:11]4[CH2:15][CH2:14][CH2:13][CH2:12]4)[CH2:7][CH2:6]3)=[O:4])[CH2:20][CH2:21]2)=[CH:27][CH:26]=1)(=[O:30])[CH3:29]
Reactant: O=C(CBr)N1CCN(C2CCCC2)CC1
Reactant: CC(=O)c1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)c1ccc(N2CCN(CC(=O)N3CCN(C4CCCC4)CC3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-bromo-1-(4-cyclopentyl-piperazin-1-yl)-ethanone (1.2 mmol), 1-(4-piperazin-1-yl-phenyl)-ethanone (1.2 mmol) and potassium carbonate (2.4 mmol) in acetonitrile (10 mL) is stirred at rt overnight. The solvent is removed in vacuo and to the residue is added DCM (40 mL) and aqueous sodium bicarbonate (15 mL). The layers are separated and aqueous layer is extracted with DCM (15 mL). The combined organic layers are dried (MgSO4) and solvent removed in vacuo to give the crude product, which is purified by PTLC (5% MeOH in DCM) to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][O:8][C:9]2[C:10]([CH2:16][OH:17])=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[H-].[Na+].I[CH3:23]>C1COCC1>[CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][O:8][C:9]2[C:10]([CH2:16][O:17][CH3:23])=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=2)=[CH:5][CH:4]=1
Reactant: CI
Reactant: COc1ccc(COc2ccc(C)nc2CO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCc1nc(C)ccc1OCc1ccc(OC)cc1
Reaction time: 1 h

Procedure:
1.55 g (6.00 mmol) of [3-(4-Methoxy-benzyloxy)-6-methyl-pyridin-2-yl]-methanol in cold 10 ml THF (0° C.) was treated 30 min with 0.41 g (10.30 mmol) of NaH (55% in oil), then 0.43 ml (6.90 mmol) of iodomethane was added and the yellow suspension stirred 1 h. An extraction (water/CH2Cl2) and a chromatography (silica gel, AcOEt/n-n-heptane) delivered 1.41 g (86%) of the title compound as a yellow oil. MS: 274.3 (MH+).
Reaction SMILES: CS(Cl)(=O)=O.[Cl:6][C:7]1[C:15]2[N:14]=[C:13]([NH:16][C:17]3[CH:18]=[N:19][C:20]([N:24]([CH3:26])[CH3:25])=[CH:21][C:22]=3[CH3:23])[N:12]([CH2:27][CH2:28][CH2:29]O)[C:11]=2[C:10]([C:31]([O:33][CH3:34])=[O:32])=[CH:9][CH:8]=1.S([O-])(=O)(=O)C.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.CN(C)C=O.C(=O)([O-])O.[Na+].C(N(CC)CC)C>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([C:31]([O:33][CH3:34])=[O:32])=[C:11]2[C:15]=1[N:14]=[C:13]1[N:16]([C:17]3[CH:18]=[N:19][C:20]([N:24]([CH3:26])[CH3:25])=[CH:21][C:22]=3[CH3:23])[CH2:29][CH2:28][CH2:27][N:12]21
Reactant: COC(=O)c1ccc(Cl)c2nc(Nc3cnc(N(C)C)cc3C)n(CCCO)c12
Agent: CS(=O)(=O)Cl
Agent: CS(=O)(=O)[O-]
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1cnc(N(C)C)cc1C
Temperature: 25 °C
Reaction time: 13 h
Yield: 58 %

Procedure:
Methanesulfonyl chloride (1.7 mL, 21.0 mmol) was added to a stirred solution of methyl 4-chloro-2-{[6-(dimethylamino)-4-methylpyridin-3-yl]amino}-1-(3-hydroxypropyl)-1H-benzimidazole-7-carboxylate (Reference example 119, 2.20 g, 5.26 mmol) and triethylamine (3.7 mL) in tetrahydrofuran (26 mL) at 0° C. The mixture was stirred at room temperature for 13 hr, and concentrated in vacuo. A mixture of the resulting mesylate, potassium carbonate (2.18 g, 15.8 mmol) in N,N-dimethylformamide (30 mL) was stirred at 80° C. for 4 hr. The mixture was diluted with aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was washed with diisopropyl ether to give the title compound as a colorless powder (1.22 g, 3.05 mmol, 58% in 2 steps).
Reaction SMILES: C([NH:4][C:5]1[C:6]([F:25])=[CH:7][C:8]([Cl:24])=[C:9]([CH:23]=1)[O:10][C:11]1[CH:22]=[CH:21][CH:20]=[CH:19][C:12]=1[O:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])(=O)C>CO>[NH2:4][C:5]1[C:6]([F:25])=[CH:7][C:8]([Cl:24])=[C:9]([CH:23]=1)[O:10][C:11]1[CH:22]=[CH:21][CH:20]=[CH:19][C:12]=1[O:13][CH2:14][C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)COc1ccccc1Oc1cc(NC(C)=O)c(F)cc1Cl
Solvent: CO
Product: COC(=O)COc1ccccc1Oc1cc(N)c(F)cc1Cl
Reaction time: 3 h
Yield: 90.3 %

Procedure:
To 10 ml of a methanol solution of a boron trifluoride methanol complex was added 0.25 g of methyl [2-(5-acetylamino-2-chloro-4-fluorophenoxy)phenoxy]acetate, and the mixture was heated and stirred for 3 hours. The reaction mixture was then concentrated. The residue was dissolved in ethyl acetate, and the solution was washed with saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, and then concentrated to give 0.2 g of methyl [2-(5-amino-2-chloro-4-fluorophenoxy)phenoxy]acetate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][O:5][NH:6][C:7](=[O:18])[C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[C:10]([Cl:15])[C:9]=1[O:16][CH3:17].[CH2:20](O)[CH2:21][CH2:22]C.C1(C)C=CC=CC=1>CCCCO.CCCCO.CCCCO.CCCCO.[Ti].CO.C1(C)C=CC=CC=1>[CH2:1]([O:2][C:3](=[O:19])[CH2:4][O:5][NH:6][C:7](=[O:18])[C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[C:10]([Cl:15])[C:9]=1[O:16][CH3:17])[CH2:20][CH2:21][CH3:22]
Reactant: COC(=O)CONC(=O)c1c(Cl)ccc(Cl)c1OC
Reactant: CCCCO
Agent: [Ti]
Solvent: CO
Solvent: Cc1ccccc1
Product: CCCCOC(=O)CONC(=O)c1c(Cl)ccc(Cl)c1OC
Temperature: 85 °C

Procedure:
To 161.8 g. of methyl[(3,6-dichloro-2-methoxybenzoyl) aminooxy]acetate was added 80 g. of n-butyl alcohol, 600 ml. of toluene, and 9.5 g. of titanium n-butoxide. The mixture was stirred and heated to 85° C. for 2 hours to drive off a methanol/toluene mixture. The heat was then maintained at 95°-100° C. to distill off n-butanol/toluene. The reaction mixture was cooled to 40° C. and 150 ml. of 1 M. HCl added. The mixture was then washed with 1 M. HCl, water, then saturated NaHCO3 solution, and then dried over MgOS4, filtered, and evaporated in vacuo to yield the title product as a white solid, m.p. 68°-71° C.
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.[CH2:16]([O:18][C:19]1[CH:24]=[C:23]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:22]=[C:21](O)[C:20]=1[C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=1)[CH3:17]>N1C=CC=CC=1>[CH2:16]([O:18][C:19]1[CH:24]=[C:23]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:22]=[C:21]([O:6][S:7]([C:10]([F:11])([F:12])[F:13])(=[O:8])=[O:9])[C:20]=1[C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=1)[CH3:17]
Reactant: CCOC(=O)c1cc(O)c(-c2ccc(F)cc2)c(OCC)c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: CCOC(=O)c1cc(OCC)c(-c2ccc(F)cc2)c(OS(=O)(=O)C(F)(F)F)c1

Procedure:
Trifluoromethanesulfonic anhydride (8.66 mL) was added at 0° C. to a mixture of ethyl 2-ethoxy-4′-fluoro-6-hydroxybiphenyl-4-carboxylate (13.0 g) and pyridine (80 mL), and the resultant mixture was stirred at the same temperature as above for 20 minutes. The reaction mixture was passed through a short silica gel (NH) column, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (15.6 g).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11]([OH:20])=[C:12]3[CH:18]=[C:17](I)[S:16][C:13]3=[N:14][CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[CH2:23]([OH:26])[C:24]#[CH:25]>C(NCC)C.[Cu](I)I.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>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11]([OH:20])=[C:12]3[CH:18]=[C:17]([C:25]#[C:24][CH2:23][OH:26])[S:16][C:13]3=[N:14][CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2sc(I)cc2c1O
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCNCC
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2sc(C#CCO)cc2c1O
Temperature: 25 °C
Reaction time: 72 h
Yield: 20 %

Procedure:
To a suspension of N-(4-chlorobenzyl)-4-hydroxy-2-iodothieno[2,3-b]pyridine-5-carboxamide (Example No. 2) (1.00 g) in diethylamine (28 mL) is added copper iodide (0.128 g) and Pd(PPh3)2Cl2 (0.032 g) followed by addition of propargyl alcohol (0.16 mL). The reaction is stirred at rt for 3 d. The reaction mixture is partitioned between H2O (100 mL) and ethyl acetate (100 mL). The organic layer is removed, and the aqueous layer is extracted with ethyl acetate (2×100 mL). Combined organic layers are washed with a saturated aqueous NH4Cl solution, dried with MgSO4, filtered, and concentrated in vacuo. The resulting orange solid is purified via column chromatography (CH2Cl2:CH3OH; 98:2, 95:5). Fractions homogeneous by TLC are combined and concentrated in vacuo to yield a pale orange solid which is recrystallized from CH2Cl2/CH3OH to yield 0.165 g (20%) of the title compound as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:13]([C:14](Cl)=[O:15])=[C:12]([CH3:17])[O:11][N:10]=1.[F:18][C:19]([F:56])([F:55])[C:20]1[CH:21]=[C:22]([CH:48]=[C:49]([C:51]([F:54])([F:53])[F:52])[CH:50]=1)[CH2:23][N:24]1[C:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:27]([Sn](CCCC)(CCCC)CCCC)[N:26]=[N:25]1>O1CCOCC1.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>[F:56][C:19]([F:18])([F:55])[C:20]1[CH:21]=[C:22]([CH:48]=[C:49]([C:51]([F:54])([F:53])[F:52])[CH:50]=1)[CH2:23][N:24]1[C:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:27]([C:14]([C:13]2[C:9]([C:3]3[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])=[N:10][O:11][C:12]=2[CH3:17])=[O:15])[N:26]=[N:25]1
Reactant: Cc1onc(-c2c(F)cccc2Cl)c1C(=O)Cl
Reactant: CCCC[Sn](CCCC)(CCCC)c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: Cc1onc(-c2c(F)cccc2Cl)c1C(=O)c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-c1ccccc1
Reaction time: 18 h
Yield: 50 %

Procedure:
Heat a mixture of 3-(2-chloro-6-fluoro-phenyl)-5-methyl-isoxazole-4-carbonyl chloride (187 mg, 0.681 mmol) and 1-(3,5-bis-trifluoromethyl-benzyl)-4-(tri-n-butylstannanyl)-5-phenyl-1H-[1,2,3]triazole (300 mg, 0.454 mmol) in the presence of PdCl2(PPh3)2 (32 mg) in degassed 1,4-dioxane (3.0 mL) at 80° C. After 18 h., concentrate in vacuo and purify the residue by chromatography on silica gel to provide the title compound (50% yield) as a light yellow foam. MS (ES) 609.0 (M++1); TLC Rf=0.1 (6% acetone in hexanes).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([C:20]4[S:21][C:22]([CH:25]5[CH2:27][CH2:26]5)=[N:23][N:24]=4)=[C:14]([C:16]([O:18]C)=O)[N:15]=[C:7]3[C:6]=2[CH:28]=1.C[O-].[Na+].C([NH2:34])=O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([C:20]4[S:21][C:22]([CH:25]5[CH2:27][CH2:26]5)=[N:23][N:24]=4)=[C:14]([C:16]([NH2:34])=[O:18])[N:15]=[C:7]3[C:6]=2[CH:28]=1
Reactant: NC=O
Reactant: COC(=O)c1nc2n(c1-c1nnc(C3CC3)s1)C1CC(C1)c1ccc(Br)cc1-2
Agent: C[O-]
Agent: [Na+]
Product: NC(=O)c1nc2n(c1-c1nnc(C3CC3)s1)C1CC(C1)c1ccc(Br)cc1-2

Procedure:
10-bromo-3-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-6,7-dihydro-5H-5,7-methanobenzo [c]imidazo[1,2-a]azepine-2-carboxamide was prepared similarly to as described in General Procedure L Methyl 10-bromo-3-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate was reacted with sodium methoxide and formamide to afford the crude title compound which was carried forward without further purification.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]2[NH:11][C:10]([C:12]3[CH:22]=[CH:21][C:15]([C:16]([O:18]CC)=[O:17])=[CH:14][CH:13]=3)=[CH:9][C:5]=2[N:6]=[CH:7][N:8]=1.[CH3:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][C:30]=1[O:31][C:32]1[CH:33]=[N:34][C:35]([CH3:38])=[CH:36][CH:37]=1)[NH2:27].C(N(C(C)C)CC)(C)C.CN1CCCC1=O>C(OCC)(=O)C.O>[ClH:2].[CH3:23][C:24]1[CH:25]=[C:26]([NH:27][C:3]2[C:4]3[NH:11][C:10]([C:12]4[CH:13]=[CH:14][C:15]([C:16]([OH:18])=[O:17])=[CH:21][CH:22]=4)=[CH:9][C:5]=3[N:6]=[CH:7][N:8]=2)[CH:28]=[CH:29][C:30]=1[O:31][C:32]1[CH:33]=[N:34][C:35]([CH3:38])=[CH:36][CH:37]=1
Reactant: Cc1ccc(Oc2ccc(N)cc2C)cn1
Reactant: CCOC(=O)c1ccc(-c2cc3ncnc(Cl)c3[nH]2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Cc1ccc(Oc2ccc(Nc3ncnc4cc(-c5ccc(C(=O)O)cc5)[nH]c34)cc2C)cn1
Temperature: 140 °C
Reaction time: 3 h
Yield: 57.7 %

Procedure:
A mixture of ethyl 4-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-6-yl)benzoate hydrochloride (1.297 g), 3-methyl-4-[(6-methylpyridin-3-yl)oxy]aniline (1.00 g), diisopropylethylamine (0.834 g) and 1-methyl-2-pyrrolidinone (12.5 mL) was stirred at 140° C. for 3 hrs, poured into water (100 mL)-ethyl acetate (150 mL) and the precipitated solid was collected by filtration. The solid was washed with ethyl acetate and dried under reduced pressure at 60° C. The obtained solid was suspended in methanol (40 mL), and 1N aqueous sodium hydroxide solution (20 mL) was added. After stirring at room temperature for 12 hrs, the solvent was evaporated under reduced pressure, and the residue was adjusted to pH 2 with 1N hydrochloric acid. The precipitated solid was collected by filtration, washed with water and dried under reduced pressure at 60° C. to give the title compound (1.08 g).