Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].C[SiH](C)C.[Br:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH2:9]Br.[Cl:15][C:16]1[CH:21]=[C:20](Cl)[N:19]=[CH:18][N:17]=1.O>O1CCCC1.BrC(Br)C.[Zn]>[Cl:15][C:16]1[CH:21]=[C:20]([CH2:9][C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[Br:6])[N:19]=[CH:18][N:17]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: BrCc1ccccc1Br
Agent: CC(Br)Br
Agent: C[SiH](C)C
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: Clc1cc(Cc2ccccc2Br)ncn1
Reaction time: 0.33 h
Yield: 30.4 %

Procedure:
In 10 ml of tetrahydrofuran was suspended 1.3 g of zinc (powder), to which dibromoethane (2 drops) was added. The mixture was heated under reflux for 5 minutes, to which trimethylsilane chloride was added. The mixture was further heated under reflux for 5 minutes, to which a solution of 2.0 g of 2-bromobenzyl bromide dissolved in 20 ml of tetrahydrofuran was slowly added with heating under reflux, followed by stirring for 20 minutes. (The solution thus obtained is referred to as solution L). In 10 ml of tetrahydrofuran were suspended 1.5 g of 4,6-dichloropyrimidine and 0.1 g of dichlorobistriphenylphosphine palladium, to which the above solution L was added, followed by heating under reflux for 3 hours and further stirring at room temperature for 12 hours. The reaction mixture was then poured into water and extracted three times with ethyl acetate. The organic layers were combined, washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.69 g of 4-chloro-6-(2-bromobenzyl)pyrimidine.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[O:13][C:12]([CH:14]([NH:18][C:19]4[CH:20]=[CH:21][C:22]([C:25]([O:27]C)=[O:26])=[N:23][CH:24]=4)[CH:15]([CH3:17])[CH3:16])=[C:11]([CH3:29])[C:10]=3[CH:30]=2)[CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+]>C(O)C>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[O:13][C:12]([CH:14]([NH:18][C:19]4[CH:20]=[CH:21][C:22]([C:25]([OH:27])=[O:26])=[N:23][CH:24]=4)[CH:15]([CH3:17])[CH3:16])=[C:11]([CH3:29])[C:10]=3[CH:30]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(NC(c2oc3ccc(OCC4CC4)cc3c2C)C(C)C)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1c(C(Nc2ccc(C(=O)O)nc2)C(C)C)oc2ccc(OCC3CC3)cc12
Yield: 81.6 %

Procedure:
To a mixture of methyl 5-({1-[5-(cyclopropylmethoxy)-3-methyl-1-benzofuran-2-yl]-2-methylpropyl}amino)pyridine-2-carboxylate (410 mg) synthesized above, tetrahydrofuran (2.0 mL) and ethanol (2.0 mL) was added 1N aqueous sodium hydroxide solution (2.0 mL), and the mixture was stirred with heating under reflux for 14 hr. The reaction mixture was concentrated under reduced pressure, water (4 mL) was added to the residue, 1N hydrochloric acid (2 mL) was added under ice-cooling, and the mixture was stirred for 20 min. The resulting precipitate was collected by filtration, and dried to give the title compound (323 mg, 80%) as a colorless solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[C:20]([CH:21]=[CH2:22])=[CH:19][N:18]=[C:17]3[N:23]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH:24]=[C:25]([NH:26][C:27]([CH:29]4[CH2:31][CH2:30]4)=[O:28])[C:16]=23)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC#N.O>C(O)C.[Pd]>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[C:20]([CH2:21][CH3:22])=[CH:19][N:18]=[C:17]3[N:23]([C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH:24]=[C:25]([NH:26][C:27]([CH:29]4[CH2:31][CH2:30]4)=[O:28])[C:16]=23)[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=Cc1cnc2c(c(NC(=O)C3CC3)cn2C(=O)OC(C)(C)C)c1N1CCC[C@@H](NC(=O)OC(C)(C)C)C1
Agent: [Pd]
Solvent: CCO
Solvent: O
Solvent: CC#N
Product: CCc1cnc2c(c(NC(=O)C3CC3)cn2C(=O)OC(C)(C)C)c1N1CCC[C@@H](NC(=O)OC(C)(C)C)C1
Reaction time: 3.5 h
Yield: 46.4 %

Procedure:
10% Pd/C (65 mg, 0.061 mmol) was added to a solution of (R)-tert-butyl 4-(3-(tert-butoxycarbonylamino)piperidin-1-yl)-3-(cyclopropanecarboxamido)-5-vinyl-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (64 mg, 0.12 mmol) in ethanol (6 mL). The mixture was stirred under a hydrogen atmosphere (balloon) for 3.5 hours. The mixture was filtered through a pad of Celite® and washed with methanol, and the filtrate evaporated in vacuo. The residue was purified by reverse phase chromatography (Biotage SP4, C-18 25M+, 15-80% CH3CN/water, 25CV) to give (R)-tert-butyl 4-(3-(tert-butoxycarbonylamino)piperidin-1-yl)-3-(cyclopropanecarboxamido)-5-ethyl-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (29.4 mg, 46% yield) as a solid. LCMS (APCI+) m/z 528 (M+H)+, Retention time=4.37 minutes.
Reaction SMILES: [CH:1]([O:3][CH2:4][CH3:5])=[CH2:2].[F:6][C:7]([F:12])([F:11])[C:8](Cl)=[O:9]>>[CH2:1]([O:3][CH:4]=[CH:5][C:8](=[O:9])[C:7]([F:12])([F:11])[F:6])[CH3:2]
Reactant: O=C(Cl)C(F)(F)F
Reactant: C=COCC
Product: CCOC=CC(=O)C(F)(F)F

Procedure:
Reaction between ethyl vinyl ether and trifluoroacetyl chloride to form 4-ethoxy-1,1,1-trifluoro-3-buten-2-one (“ETFBO”) in the absence of an acid-capturing agent and in the presence of a stabilizer for the alkenone that is to be prepared.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N:9]([S:22]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)(=[O:24])=[O:23])[C@H:10]([CH3:21])[CH2:11][CH2:12][CH2:13][C:14]([O:16]C(C)(C)C)=[O:15].FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N:9]([S:22]([C:25]1[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=1)(=[O:24])=[O:23])[C@H:10]([CH3:21])[CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15]
Reactant: C[C@H](CCCC(=O)OC(C)(C)C)N(c1cc(Cl)ccc1Cl)S(=O)(=O)c1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](CCCC(=O)O)N(c1cc(Cl)ccc1Cl)S(=O)(=O)c1ccc(Cl)cc1

Procedure:
1,1-dimethylethyl(5R)-5-[(2,5-dichlorophenyl)-[(4-chlorophenyl)sulfonyl]-amino]hexanoate (700 g, 1.40 mmol) was treated with a 50% solution of trifluoroacetic acid in dichloromethane (20 mL). After 3 h the reaction was diluted with dichloromethane then washed with water, brine and dried over MgSO4. Concentration under reduced pressure afforded (5R)-5-[(2,5-dichlorophenyl][(4-chlorophenyl)sulfonyl]-amino]hexanoic acid in quantitiative yield. MS (ESI), (M−H−) 450. IR-2975,1706,1466,1348.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11](=O)[N:10]2[N:13]=[CH:14][C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=3)=[C:9]2[NH:8][CH:7]=1)=[O:5])[CH3:2].C(OC(C1C=C([Cl:34])N2N=CC=C2N=1)=O)C>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[N:10]([N:13]=[CH:14][C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)[C:11]=1[Cl:34])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(Cl)n2nccc2n1
Reactant: CCOC(=O)c1c[nH]c2c(-c3cccc(Cl)c3)cnn2c1=O
Product: CCOC(=O)c1cnc2c(-c3cccc(Cl)c3)cnn2c1Cl

Procedure:
This compound was synthesized from 7-oxo-3-(3-chlorophenyl)-4,7-dihydro-pyrazolo-[1,5-a]-pyrimidine-6-carboxylic acid ethyl ester, according to the process for synthesizing the foregoing 7-chloro-pyrazolo-[1,5-a]-pyrimidine-5-carboxylic acid ethyl ester. mp: 140-141° C.
Reaction SMILES: [OH:1][N:2]=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]([CH2:45][CH:46]2[CH2:50][CH2:49][CH2:48][N:47]2C(OC(C)(C)C)=O)[CH2:14][C@@H:15]([OH:44])[C@@H:16]([NH:24][C:25](=[O:43])[C@@H:26]([N:30]2[CH2:34][CH2:33][N:32]([CH2:35][C:36]3[N:37]=[C:38]([CH3:41])[S:39][CH:40]=3)[C:31]2=[O:42])[CH:27]([CH3:29])[CH3:28])[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1>ClCCl.FC(F)(F)C(O)=O>[CH2:17]([C@H:16]([NH:24][C:25](=[O:43])[C@@H:26]([N:30]1[CH2:34][CH2:33][N:32]([CH2:35][C:36]2[N:37]=[C:38]([CH3:41])[S:39][CH:40]=2)[C:31]1=[O:42])[CH:27]([CH3:29])[CH3:28])[C@H:15]([OH:44])[CH2:14][N:13]([S:10]([C:7]1[CH:8]=[CH:9][C:4](/[CH:3]=[N:2]/[OH:1])=[CH:5][CH:6]=1)(=[O:11])=[O:12])[CH2:45][CH:46]1[CH2:50][CH2:49][CH2:48][NH:47]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Cc1nc(CN2CCN([C@H](C(=O)N[C@@H](Cc3ccccc3)[C@H](O)CN(CC3CCCN3C(=O)OC(C)(C)C)S(=O)(=O)c3ccc(C=NO)cc3)C(C)C)C2=O)cs1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nc(CN2CCN([C@H](C(=O)N[C@@H](Cc3ccccc3)[C@H](O)CN(CC3CCCN3)S(=O)(=O)c3ccc(/C=N/O)cc3)C(C)C)C2=O)cs1
Yield: 94.8 %

Procedure:
A solution of the product of Example 274E (12 mg) in dichloromethane (0.5 mL) and trifluoroacetic acid (0.5 mL) was stirred at 25° C. for 1 hour and concentrated. The residue was purified by HPLC reverse phase chromatography using water (0.1% trifluoroacetic acid):acetonitrile (95:5) to acetonitrile (100%) to give 10 mg (95%) of the title compound.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:6]2[CH:15]=[CH:14][C:13]([O:16]C)=[CH:12][C:7]=2[O:8][C:9]=1[CH2:10][CH3:11])=[O:4].B(Br)(Br)Br>>[CH3:1][NH:2][C:3]([C:5]1[C:6]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:7]=2[O:8][C:9]=1[CH2:10][CH3:11])=[O:4]
Reactant: CCc1oc2cc(OC)ccc2c1C(=O)NC
Agent: BrB(Br)Br
Product: CCc1oc2cc(O)ccc2c1C(=O)NC
Yield: 84.3 %

Procedure:
Example 14(c) was prepared from 6-methoxy-2-ethylbenzo[b]furan-3-carboxylic acid methylamide 14b (401 mg, 1.72 mmole) by treatment with BBr3 in a manner as previously described for example 1d to give 318 mg (84%) of an off-white solid. 1H NMR (DMSO-d6) δ 9.53 (1H, s), 7.79 (1H, d, J=4.6 Hz), 7.45 (1H, d, J=8.6 Hz), 6.88 (1H, d, J=2.0 Hz), 6.74 (1H, dd, J=2.0, 8.6 Hz), 3.03 (2H, q, J=7.3 Hz), 2.77 (3H, d, J=4.6 Hz), 1.24 (3H, t, J=7.3 Hz). Anal. Calcd for C12H13NO3: C, 65.74; H, 5.98; N, 6.39. Found: C, 65.61; H, 6.06; N, 6.32.
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=2[CH2:21][N:22]2[C@@H:26]([CH3:27])[C@@H:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:24][C:23]2=[O:34])[CH:6]=1.COC1C=C(B(O)O)C=CC=1>>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([O:13][C:7]2[CH:6]=[C:5]([CH2:4][C:3]([OH:35])=[O:2])[CH:10]=[CH:9][C:8]=2[O:11][CH3:12])=[C:15]([CH2:21][N:22]2[C@@H:26]([CH3:27])[C@@H:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:24][C:23]2=[O:34])[CH:16]=1
Reactant: COC(=O)Cc1ccc(OC)c(Oc2ccc(Br)cc2CN2C(=O)O[C@H](c3ccccc3)[C@@H]2C)c1
Agent: COc1cccc(B(O)O)c1
Product: COc1ccc(CC(=O)O)cc1Oc1ccc(Br)cc1CN1C(=O)O[C@H](c2ccccc2)[C@@H]1C

Procedure:
Prepared according to the procedure described in Example 19, Step 3, using the following starting materials: {3-[4-bromo-2-((4S,5R)-4-methyl-2-oxo-5-phenyl-oxazolidin-3-ylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid methyl ester and 3-methoxyphenylboronic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.[NH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[N:16][C:17]([Cl:23])=[CH:18][CH:19]=2)[N:14]=1.C(#N)C>O>[Cl:23][C:17]1[N:16]=[C:15]2[C:20]([CH:21]=[CH:22][C:13]([NH:12][C:7](=[O:9])[C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=3)=[N:14]2)=[CH:19][CH:18]=1
Reactant: COc1ccc(C(=O)O)cc1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Solvent: O
Solvent: CC#N
Product: COc1ccc(C(=O)Nc2ccc3ccc(Cl)nc3n2)cc1
Temperature: 4 °C
Yield: 55.7 %

Procedure:
The procedure is similar to that described in Example 1, but starting with 4-methoxybenzoic acid (4.6 g), N,N'-carbonyldiimidazole (4.9 g) and 2-amino-7-chloro-1,8-naphthyridine (3.6 g). The product produced by precipitation in water (4.3 g; m.p. 208° C.) is dissolved in boiling acetonitrile (660 cc). After 3 hours' cooling at 4° C., the crystallised solid is separated by filtration, washed with acetonitrile (3×20 cc) and dried at 50° C. under reduced pressure (0.067 kPa). N-(7-chloro-1,8-naphthyridin-2-yl)-4-methoxybenzamide (3.5 g) is produced, m.p. 208° C.
Reaction SMILES: N12CCCN=C1CCCCC2.[N+:12]([C:15]1[CH:16]=[C:17]([CH2:21][C:22]([O:24][CH2:25][CH:26]=[CH2:27])=[O:23])[CH:18]=[CH:19][CH:20]=1)([O-:14])=[O:13].C(NC1C=CC(S([N:41]=[N+:42]=[N-])(=O)=O)=CC=1)(=O)C>C1COCC1>[N+:41](=[C:21]([C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([N+:12]([O-:14])=[O:13])[CH:16]=1)[C:22]([O:24][CH2:25][CH:26]=[CH2:27])=[O:23])=[N-:42]
Reactant: C=CCOC(=O)Cc1cccc([N+](=O)[O-])c1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: C=CCOC(=O)C(=[N+]=[N-])c1cccc([N+](=O)[O-])c1
Temperature: 23 °C
Reaction time: 18 h
Yield: 94.4 %

Procedure:
To a solution of 1,8-diazabicyclo[5.4.0]undec-7-ene (10.6 g, 10.5 ml, 69.6 mmol, Eq: 1.04) in THF (59.0 ml) at 5° C. was added dropwise a solution of allyl 2-(3-nitrophenyl)acetate (intermediate B3a) (14.8 g, 66.9 mmol, Eq: 1.00) and 4-acetamidobenzenesulfonyl azide (16.6 g, 68.9 mmol, Eq: 1.03) in THF (118 ml) within 40 min and the mixture was stirred at 23° C. for 18 h protected from light. Quenched with sat. NH4Cl-sol., diluted with ethyl acetate, separated phases, the organic layer was washed with brine and dried over Na2SO4. Removal of the solvent in vacuum left an orange semisolid, diluted with diethyl ether, filtered the solid off, washed with diethyl ether, the filtrate was concentrated in vacuum to give an orange semisolid. The crude material was purified by flash chromatography (silica gel, 300 g, 25% to 30% EtOAc in heptane) to give the title compound as a yellow solid (15.62 g, 94%).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([OH:12])[CH:8]=[C:9]([CH3:11])[CH:10]=1)[CH:2]=[CH2:3].F[C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1>>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:8]=[C:9]([CH3:11])[CH:10]=1)[O:12][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1cc(C)cc(O)c1
Reactant: O=Cc1ccc(F)cc1
Product: C=CCOc1cc(C)cc(Oc2ccc(C=O)cc2)c1

Procedure:
The product from Example 89A and 4-fluorobenzaldehyde were processed as in Example 61C to provide the title compound. MS (DCI) m/z 269 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](I)[C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:14]([NH:16][CH:17]1[CH2:19][CH2:18]1)=[O:15].[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[C:22]=1B(O)O>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:22]3[C:23]([O:27][CH3:28])=[CH:24][CH:25]=[CH:26][C:21]=3[F:20])[C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:14]([NH:16][CH:17]1[CH2:19][CH2:18]1)=[O:15]
Reactant: Nc1c(C(=O)NC2CC2)nnc2c(I)c(F)ccc12
Reactant: COc1cccc(F)c1B(O)O
Product: COc1cccc(F)c1-c1c(F)ccc2c(N)c(C(=O)NC3CC3)nnc12
Yield: 31.6 %

Procedure:
Using Method G, 4-amino-7-fluoro-8-iodo-N-cyclopropyl-cinnoline-3-carboxamide (372 mg, 1.00 mmol) and 2-fluoro-6-methoxyphenylboronic acid (1.40 g, 8.24 mmol) were reacted. After purification the title compound (117 mg, 33% yield) was obtained as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.50 (bm, 1H), 7.94 (dd, J=5.2, 9.2 Hz, 1H), 7.53 (a t, J=8.7 Hz, 1H), 7.40 (apparent q, J=7.8 Hz, 1H), 6.86 (m, 2H), 3.72 (s, 3H), 2.96 (m, 1H), 0.88 (m, 2H), 0.62 (m, 2H). MS APCI, m/z=371.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[N:14][CH:13]=[CH:12][N:11]=2)[C:7]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)=[N:6]1.[NH:26]1[CH2:31][CH2:30][CH:29]([N:32]2[C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=3[O:35][CH2:34][C:33]2=[O:42])[CH2:28][CH2:27]1.C(N(CC)CC)C>CCO>[OH:1][CH:2]([CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[N:14][CH:13]=[CH:12][N:11]=2)[C:7]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:24])([F:25])[F:23])=[CH:18][CH:17]=2)=[N:6]1)[CH2:3][N:26]1[CH2:27][CH2:28][CH:29]([N:32]2[C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=3[O:35][CH2:34][C:33]2=[O:42])[CH2:30][CH2:31]1
Reactant: O=C1COc2ccccc2N1C1CCNCC1
Reactant: FC(F)(F)c1ccc(-c2nn(CC3CO3)cc2-c2cnccn2)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C1COc2ccccc2N1C1CCN(CC(O)Cn2cc(-c3cnccn3)c(-c3ccc(C(F)(F)F)cc3)n2)CC1
Temperature: 80 °C
Yield: 21.2 %

Procedure:
To a solution of 2-[1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-1H-pyrazol-4-yl]-pyrazine (76 mg, 0.220 mmol) and 4-piperidin-4-yl-4H-benzo[1,4]oxazin-3-one (61 mg, 0.231 mmol) in EtOH (1.1 mL) was added triethylamine (0.031 mL, 0.220 mmol). The reaction mixture was heated to 80° C. overnight, concentrated, and purified by column chromatography (silica, 5-10% MeOH/CH2Cl2) to afford 4-(1-{2-hydroxy-3-[4-pyrazin-2-yl-3-(4-trifluoromethyl-phenyl)-pyrazol-1-yl]-propyl}-piperidin-4-yl)-4H-benzo[1,4]oxazin-3-one (27 mg, 21%). TLC (silica, 5% MeOH/CH2Cl2): Rf=0.09. MS (electrospray): m/z 579.2 (579.2, calculated for C30H29F3N6O3, M++H). 1H NMR (400 MHz, CDCl3): 8.53 (s, 1H), 8.48 (s, 1H), 8.40 (s, 1H), 8.11 (s, 1H), 7.73 (d, J=8.2 Hz, 2H), 7.63 (d, J=8.2 Hz, 2H), 7.16 (d, J=5.4 Hz, 1H), 7.00-7.03 (m, 3H), 4.49 (s, 2H), 4.39 (d, J=10.8 Hz, 1H), 3.13 (d, J=11.9 Hz, 1H), 2.96 (d, J=11.9 Hz, 1H), 2.59-2.80 (m, 2H), 2.40-2.55 (m, 3H), 2.17 (t, J=11.9 Hz, 1H),1.77 (d, J=11.9 Hz, 2H).
Reaction SMILES: [CH3:1][C:2]1[N:11]([N:12]2[C:24](=[O:25])[C:22]3[C:23]4[N:15]([C:16]([N+:26]([O-])=O)=[CH:17][C:18]=4[CH2:19][CH2:20][CH:21]=3)[C:14]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:13]2)[C:10](=[O:35])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[OH-].[Na+]>[Cl-].[Cl-].[Cl-].[Ti+3].C(O)(=O)C>[NH2:26][C:16]1[N:15]2[C:14]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:13][N:12]([N:11]3[C:10](=[O:35])[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[N:3]=[C:2]3[CH3:1])[C:24](=[O:25])[C:22]3=[CH:21][CH2:20][CH2:19][C:18]([CH:17]=1)=[C:23]23
Reactant: Cc1nc2ccccc2c(=O)n1N1C=C(c2ccccc2)n2c([N+](=O)[O-])cc3c2C(=CCC3)C1=O
Agent: [Ti+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1nc2ccccc2c(=O)n1N1C=C(c2ccccc2)n2c(N)cc3c2C(=CCC3)C1=O
Reaction time: 0.5 h

Procedure:
An alternative process consists in using titanium trichloride as reducing agent. Thus, in a reactor under nitrogen, protected from moisture and equipped with a magnetic stirrer, 5.0 g (10.7 minol) of the product of Example 20 are introduced into 42.8 ml of acetic acid. 64 mmol of TiCl3 (in 30% solution in 2N HCl) are added dropwise and the mixture is kept stirring for 30 min. It is then alcalinized with sodium hydroxide to a pH of 9, the medium being cooled by adding ice.
Reaction SMILES: [S:1]1[C:10]2[CH2:9][CH2:8][CH2:7][C:6](=O)[NH:5][C:4]=2[CH:3]=[CH:2]1.B.CSC.CO>O1CCCC1>[N:5]1[C:4]2[CH2:10][S:1][CH2:2][C:3]=2[CH2:9][CH2:8][CH2:7][CH:6]=1
Reactant: O=C1CCCc2sccc2N1
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Solvent: CO
Product: C1=NC2=C(CCC1)CSC2
Temperature: 0 °C
Reaction time: 16 h
Yield: 79.3 %

Procedure:
To a mixture of 21.2 g of 5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepin-5-one in 100 ml of tetrahydrofuran under argon, chilled to 0° C. is added 25.2 ml of a 10.0 molar solution of borane-dimethylsulfide in tetrahydrofuran. The solution is stirred at room temperature for 16 hours and is refluxed for 5 hours. The mixture is cooled to room temperature and 85 ml of methanol added dropwise (exotherm). The solvent is removed and 100 ml of methanol is added (2 times) and after each addition the solvent is removed. To the residual solid (dried under vacuum) is added 126 ml of 2N NaOH and the mixture refluxed 3 hours. The mixture is chilled (2 hours) and extracted with dichloromethane. The extract is dried (Na2SO4) and the solvent removed to give 15.4 g of brown solid, m.p. 55°-57° C. A sample (3 g) is sublimed to give 2.6 g of crystals, m.p. 64°-65° C.
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH2:13])[C:8]=2[NH:14][C:15](=[O:19])[O:16][CH2:17][CH3:18])=[CH:4][C:3]=1[F:22].[H-].[Na+].[CH3:25]I>C1COCC1>[NH2:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH2:13])[C:8]=2[N:14]([CH3:25])[C:15](=[O:19])[O:16][CH2:17][CH3:18])=[CH:4][C:3]=1[F:22]
Reactant: CI
Reactant: CCOC(=O)Nc1c(Oc2ccc(N)c(F)c2)ccnc1N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)N(C)c1c(Oc2ccc(N)c(F)c2)ccnc1N
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
Ethyl 4-(4-amino-3-fluorophenoxy)-2-aminopyridin-3-yl-carbamate (6a) (480 mg, 1.6 mmol) was dissolved in dry THF (8 mL) and cooled at 0° C. Sodium hydride (60% in mineral oil, 80 mg, 2.0 mmol) was added, and the reaction mixture was stirred for 40 minutes at 0° C. Methyl iodide (130 μL, 1.8 mmol) was added at 0° C. The ice bath was removed, and the mixture was stirred at room temperature for 18 hours. The solvent was evaporated and the residue partitioned between DCM and distilled water. The organic layer was dried and evaporated, and the residue washed with diethyl ether to afford the title compound as a brown solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:32])[CH:9]1[CH2:14][CH2:13][CH:12]([O:15][C:16]2[C:27]3[C:26]4[C@@H:25]([CH2:28][C:29]([OH:31])=O)[CH2:24][CH2:23][C:22]=4[S:21][C:20]=3[N:19]=[CH:18][N:17]=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=[N:39]C=2C=1.CCN=C=NCCCN(C)C.[NH4+].[Cl-]>CN(C=O)C.CN(C)C1C=CN=CC=1.O>[C:29]([CH2:28][C@H:25]1[CH2:24][CH2:23][C:22]2[S:21][C:20]3[N:19]=[CH:18][N:17]=[C:16]([O:15][CH:12]4[CH2:13][CH2:14][CH:9]([N:8]([CH3:32])[C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:10][CH2:11]4)[C:27]=3[C:26]1=2)(=[O:31])[NH2:39]
Reactant: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](CC(=O)O)CC4)CC1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](CC(N)=O)CC4)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 80 %

Procedure:
For the preparation of the starting material 35.1, please see Example 35. Into a 50-mL round-bottom flask containing a solution of 2-[(3R)-12-[(4-[[(tert-butoxy)carbonyl](methyl)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 (220 mg, 0.48 mmol, 1.00 equiv) in 4 mL of distilled DMF was added HOBT (96.6 mg), 4-dimethylaminopyridine (86.6 mg), EDCI (136.7 mg) and NH4Cl (153.18 mg, 2.86 mmol, 6.01 equiv) successively at room temperature under nitrogen. The resulting solution was stirred for 14 hr at 25° C. and diluted with water, extracted with 3×50 mL of ethyl acetate. The combined organic layers was washed with 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 tert-butyl N-(4-[[(3R)-3-(carbamoylmethyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (176 mg, 80%) as a colorless oil. MS (ES): m/z 461 [M+H]+.