Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6](=[O:9])[CH2:7][CH2:8][C:2]1=2.[H-].[Na+].C(OC(=O)[C:16]1C=CC=[C:18]([F:22])[CH:17]=1)C.Cl.[CH2:25]1[CH2:29][O:28][CH2:27][CH2:26]1>C(OCC)(=O)C.O>[F:22][C:18]1[CH:27]=[CH:26][C:25]([C:29]([CH:7]2[CH2:8][C:2]3[S:1][CH:5]=[CH:4][C:3]=3[C:6]2=[O:9])=[O:28])=[CH:16][CH:17]=1
Reactant: O=C1CCc2sccc21
Reactant: CCOC(=O)c1cccc(F)c1
Reactant: C1CCOC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(c1ccc(F)cc1)C1Cc2sccc2C1=O
Temperature: 100 °C
Yield: 14 %

Procedure:
5,6-Dihydro-cyclopenta[b]thiophen-4-one (2.1 g, 15.0 mmol) in 15 mL of THF was treated with NaH (60 percent, 1.5 g, 36 mmol). After the addition of 3-Fluoro-benzoic acid ethyl ester, the reaction mixture was heated at 100° C. for 8 hr. The solution was cooled to room temperature and poured into water. The resulting mixture was acidified with concentrated HCl and was added with ethyl acetate (70 mL). The organic layer was collected, brined, dried over MgSO4(s), and concentrated under reduced pressure. The resultant precipitate was collected and recrystallized from ethanol to provide the corresponding 5-(4-Fluoro-benzoyl)-5,6-dihydro-cyclopenta[b]thiophen-4-one (0.56 g, 2.1 mmol) as brown solid in 14% yield.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][O:7]S(C)(=O)=O.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[C:19]([C:26]2[C:35]3[C:30](=[CH:31][C:32](O)=[CH:33][CH:34]=3)[N:29]=[CH:28][CH:27]=2)=[C:20]2[CH2:25][CH2:24][CH2:23][N:21]2[N:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[C:19]([C:26]2[C:35]3[C:30](=[CH:31][C:32]([O:7][CH2:6][CH:2]4[CH2:3][CH2:4][CH2:5][O:1]4)=[CH:33][CH:34]=3)[N:29]=[CH:28][CH:27]=2)=[C:20]2[CH2:25][CH2:24][CH2:23][N:21]2[N:22]=1
Reactant: Oc1ccc2c(-c3c(-c4ccccn4)nn4c3CCC4)ccnc2c1
Reactant: CS(=O)(=O)OCC1CCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: c1ccc(-c2nn3c(c2-c2ccnc4cc(OCC5CCCO5)ccc24)CCC3)nc1
Temperature: 60 °C

Procedure:
A mixture of methanesulfonic acid tetrahydro-furan-2-ylmethyl ester (0.70 g, 3.66 mmol), 4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-ol (400 mg, 1.22 mmol), and cesium carbonate (2.38 g, 7.32 mmol) in N,N-dimethylformamide (2.5 mL) is heated at 60° C. for 42 h. The mixture is concentrated in vacuo and the residue chromatographed to yield the title compound, 79 mg (15%), as a tan solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([CH2:30][C:31](O)=[O:32])[C:25]=1[CH3:34])(=[O:12])=[O:11].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[CH:49]1([NH:52][C:53]([C@@H:55]2[CH2:59][C@@H:58]([OH:60])[CH2:57][NH:56]2)=[O:54])[CH2:51][CH2:50]1>CN(C=O)C.C(Cl)Cl>[CH:49]1([NH:52][C:53]([C@@H:55]2[CH2:59][C@@H:58]([OH:60])[CH2:57][N:56]2[C:31](=[O:32])[CH2:30][C:26]2[C:25]([CH3:34])=[C:24](/[CH:23]=[C:16]3\[C:17](=[O:22])[NH:18][C:19]4[C:15]\3=[CH:14][C:13]([S:10]([CH2:9][C:3]3[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])(=[O:11])=[O:12])=[CH:21][CH:20]=4)[NH:28][C:27]=2[CH3:29])=[O:54])[CH2:51][CH2:50]1
Reactant: O=C(NC1CC1)[C@@H]1C[C@@H](O)CN1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CC(=O)O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: ClCCCl
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CC(=O)N1C[C@H](O)C[C@H]1C(=O)NC1CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a mixture of {5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-acetic acid (238 mg, 0.46 mmol), HOBt (68 mg, 0.51 mmol) and EDC (105 mg, 0.55 mmol) in DMF 98 mL) was added (2S,4R)-4-hydroxy-pyrrolidine-2-carboxylic acid cyclopropylamide (excess) and TEA (0. 95 mL, 0.6 mmol). The mixture was stirred at rt for 3 days. The reaction was diluted with DCM (200 mL), washed with NH4Cl, NaHCO3, brine, dried and concentrated. The residue was purified on a silica gel column to give 120 mg of the titled compound. MS m/z 655 [M−1].
Reaction SMILES: [CH:1]([C:3]1[CH2:9][C:8]2[CH:10]=[C:11]3[O:16][CH2:15][O:14][C:12]3=[CH:13][C:7]=2[C:6]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)=[N:5][N:4]=1)=[O:2].O.B([O-])=O.[Na+]>C1COCC1>[OH:2][CH2:1][C:3]1[CH2:9][C:8]2[CH:10]=[C:11]3[O:16][CH2:15][O:14][C:12]3=[CH:13][C:7]=2[C:6]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)=[N:5][N:4]=1
Reactant: O=CC1=NN=C(c2ccc([N+](=O)[O-])cc2)c2cc3c(cc2C1)OCO3
Agent: O=B[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(C2=NN=C(CO)Cc3cc4c(cc32)OCO4)cc1
Temperature: 20 °C
Yield: 78.4 %

Procedure:
2.5 g (7.41 mmol) of 8-formyl-5-(4-nitrophenyl)-9H-1,3-dioxolo[4,5-h][2,3]benzodiazepine (I, stage A) is suspended in THF:water=1:1 and mixed with 0.14 g (3.7 mmol) of sodium boranate while being stirred and cooled to 20° C. After 45 minutes of stirring, it is filtered and the crude product is precipitated from the filtrate with 130 ml of water. 2.35 g, which is recrystallized from a mixture of 6.3 ml of dimethylformamide and 1.3 ml of water, is obtained. 1.97 g (78%) of the title compound with a melting point of 175° C. (decomposition) is obtained.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[CH:6][C:5]([Cl:23])=[CH:4][N:3]=1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=1[OH:32]>>[Cl:23][C:5]1[CH:6]=[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])[C:2]([O:32][C:26]2[CH:27]=[C:28]([Cl:31])[CH:29]=[CH:30][C:25]=2[Cl:24])=[N:3][CH:4]=1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Cl)cc1
Reactant: Oc1cc(Cl)ccc1Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Oc2cc(Cl)ccc2Cl)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 45 from methyl 4-((1S)-1-{[(2,5-dichloropyridin-3-yl)carbonyl]amino}ethyl)benzoate (step 1 of Example 48) and 2,5-dichlorophenol: 1H-NMR (CDCl3) δ 8.55 (1H, d, J=2.8 Hz), 8.34 (1H, d, J=2.6 Hz), 8.27–7.99 (3H, m), 7.46–7.43 (3H, m), 7.35 (1H, d, J=2.3 Hz), 7.29–7.25 (1H, m), 5.44–5.34 (1H, m), 3.90 (3H, s), 1.61 (3H, d, J=6.9 Hz).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([NH:11][CH2:12][C@@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[N:7][C:6]=12.[NH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1>>[NH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:2]2[CH:3]=[N:4][N:5]3[CH:10]=[CH:9][C:8]([NH:11][CH2:12][C@@H:13]4[CH2:17][CH2:16][CH2:15][N:14]4[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[N:7][C:6]=23)=[CH:29][CH:28]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CNc1ccn2ncc(Br)c2n1
Reactant: NCc1ccc(B(O)O)cc1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1CNc1ccn2ncc(-c3ccc(CN)cc3)c2n1
Yield: 73 %

Procedure:
The Suzuki coupling of (5)-tert-butyl 2-(((3-bromopyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)pyrrolidine-1-carboxylate with (4-(aminomethyl)phenyl)boronic acid under the same conditions as described in example 5.6.5 to give 73% of the titled compound. 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.44 (br. s., 9 H) 1.90 (dd, J=9.92, 5.51 Hz, 1 H) 1.96-2.11 (m, 3 H) 3.35-3.45 (m, 4 H) 4.07-4.21 (m, 3 H) 6.33 (br. s., 1 H) 7.46 (d, J=8.38 Hz, 2 H) 8.19 (br. s., 2 H) 8.25-8.36 (m, 2 H); LRMS (ESI) m/e 423.0 [(M+H)+, calcd for C23H30N6O2 422.0].
Reaction SMILES: [C:1]1(C)[C:2]([SH:7])=[CH:3][CH:4]=[CH:5][CH:6]=1.[OH-].[K+].[CH2:11]([O:13][CH:14]([O:17][CH2:18][CH3:19])[CH2:15]Br)[CH3:12].[CH2:20](OCC)C>C(O)C>[CH2:11]([O:13][CH:14]([O:17][CH2:18][CH3:19])[CH2:15][S:7][C:2]1[CH:1]=[CH:6][CH:5]=[C:4]([CH3:20])[CH:3]=1)[CH3:12]
Reactant: Cc1ccccc1S
Reactant: CCOC(CBr)OCC
Reactant: CCOCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(CSc1cccc(C)c1)OCC
Temperature: 0 °C

Procedure:
In 90 mL of ethanol is dissolved 25 g of toluenethiol, to which are added 12.42 g of potassium hydroxide and 33.3 mL of bromoacetaldehyde diethyl acetal. The mixture thus obtained is heated under reflux for 2.5 hours. The reaction mixture is introduced into a mixture of ice water and diethyl ether, and the organic layer is separated. The organic layer is washed with saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure, and the residue is distilled under reduced pressure (113-125° C./2.5 mm Hg) to obtain 41.5 g of 1-[(2,2-diethoxyethyl)sulfanyl]-3-methylbenzene as an oily product.
Reaction SMILES: [CH3:1][CH2:2][O:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[C:15]([CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=[O:16].[C:23]([CH2:27][O:28][CH2:29][CH2:30]Br)([O:25][CH3:26])=[O:24].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:1][CH2:2][O:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[C:15]([CH:17]1[CH2:18][CH2:19][N:20]([CH2:30][CH2:29][O:28][CH2:27][C:23]([O:25][CH3:26])=[O:24])[CH2:21][CH2:22]1)=[O:16]
Reactant: CCOCCn1c(C(=O)C2CCNCC2)nc2ccccc21
Reactant: COC(=O)COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOCCn1c(C(=O)C2CCN(CCOCC(=O)OC)CC2)nc2ccccc21
Temperature: 90 °C

Procedure:
Mix 1-[[(2-ethoxy)ethyl]-1H-benzimidazol-2-yl][1-(4-piperidinyl)]methanone (3.89 g, 12.91 mmol), carbomethoxy methoxy ethylbromide (3.01 g, 15.3 mmol), potassium carbonate (5.29 g, 38.25 mmol) and dimethylformamide (100 mL). Stir and heat and at 90° C. overnight. Allow to cool to room temperature, dilute with water and extract with ethyl acetate (2×). Wash the combined organic phases with water (3×), then brine and dry (MgSO4). Evaporate the solvent in vacuo to give and purify by chromatography to give the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1)#[CH:2].[C:12]1(C)C=CC(S(O)(=O)=O)=C[CH:13]=1.C([NH:25][CH2:26][C@H:27]([NH:31][S:32]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)(=[O:34])=[O:33])[C:28]([OH:30])=[O:29])C.CN1CCOCC1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[CH2:12]([O:30][C:28](=[O:29])[C@@H:27]([NH:31][S:32]([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)(=[O:33])=[O:34])[CH2:26][NH:25][C:7](=[O:9])[C:6]1[CH:5]=[CH:4][C:3]([C:1]#[CH:2])=[CH:11][CH:10]=1)[CH3:13]
Reactant: CCNC[C@H](NS(=O)(=O)c1ccccc1)C(=O)O
Reactant: C#Cc1ccc(C(=O)O)cc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: C#Cc1ccc(C(=O)NC[C@H](NS(=O)(=O)c2ccccc2)C(=O)OCC)cc1
Reaction time: 8 h

Procedure:
4-Ethynylbenzoic acid (35-1) (3.10 g, 21.2 mmol), 35-2 (8.58 g, 19.3 mmol), NMM (8.49 mL, 7.72 mmol), HOBT (3.39 g, 25.1 mmol), and EDC (4.81 g, 25.1 mmol) were combined in 96 mL DMF and stirred overnight. The reaction was concentrated, residue was diluted with EtOAc and washed with water (2×) and brine, dried (Na2SO4), filtered, and concentrated. Flash chromatography (silica, 45-50% EtOAc/Hexane) gave 35-3 as a white solid.
Reaction SMILES: Br[CH:2](C)[C:3]([C:8]1[CH:9]=[CH:10][C:11]([S:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:12]([CH2:14][C:15]([O-:17])=[O:16])[CH:13]=1)(OC)OC.[C:26](=O)([O-:28])[OH:27].[Na+].C(O)C>O>[C:26]([CH:3]([C:8]1[CH:9]=[CH:10][C:11]([S:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[C:12]([CH2:14][C:15]([OH:17])=[O:16])[CH:13]=1)[CH3:2])([OH:28])=[O:27]
Reactant: O=C([O-])O
Reactant: COC(OC)(c1ccc(Sc2ccccc2)c(CC(=O)[O-])c1)C(C)Br
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C(=O)O)c1ccc(Sc2ccccc2)c(CC(=O)O)c1
Reaction time: 5 h
Yield: 13.6 %

Procedure:
A mixture of 4.39 g (10 mol.) of 5-(2-bromo-1,1-dimethoxypropyl)-2-phenylthiophenylacetate obtained in Example 1-(2), 4.20 g (50 mmol.) of sodium hydrogen carbonate, 50 ml of ethanol and 35 ml of water was heated under reflux and stirring for 5 hours. The reaction mixture was distilled to remove distillates having a boiling point of below 100° C. The residue was then heated under reflux for 4 hours. The mixture was treated in the same manner as in Example 6-(1) to obtain 2.15 g of the desired product as white crystals (yield 68%), m.p. 145°-146° C.
Reaction SMILES: [OH:1][CH:2]1[C:7]([O:10][CH3:11])([O:8][CH3:9])[CH2:6][CH2:5][N:4]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:3]1.[H-].[Na+].C1(C)C=CC(S(O[CH2:31][CH2:32][F:33])(=O)=O)=CC=1>CN(C=O)C>[F:33][CH2:32][CH2:31][O:1][CH:2]1[C:7]([O:8][CH3:9])([O:10][CH3:11])[CH2:6][CH2:5][N:4]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:3]1
Reactant: COC1(OC)CCN(C(=O)OC(C)(C)C)CC1O
Reactant: Cc1ccc(S(=O)(=O)OCCF)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1(OC)CCN(C(=O)OC(C)(C)C)CC1OCCF
Yield: 97.7 %

Procedure:
The same operation as in Example (90a) was performed using tert-butyl 3-hydroxy-4,4-dimethoxypiperidine-1-carboxylate (6.2 g, 23.7 mmol), sodium hydride (55% content, 1.57 g, 36 mmol), 2-fluoroethyl p-toluenesulfonate (7.85 g, 46 mmol) and DMF (50 mL). The residue was purified by column chromatography (elution solvent: hexane/ethyl acetate=10/1, 4/1, 2/1) to obtain 7.12 g of the title compound as a colorless oily substance (98%).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([NH:13][CH2:14][CH3:15])[C:5]([C:6](OCC)=[O:7])=[CH:4][N:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH2:6][OH:7])=[C:11]([NH:13][CH2:14][CH3:15])[CH:12]=1
Reactant: CCNc1cc(Cl)ncc1C(=O)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCNc1cc(Cl)ncc1CO
Temperature: 0 °C
Reaction time: 1 h
Yield: 78.8 %

Procedure:
A −50° C. solution of ethyl 6-chloro-4-(ethylamino)nicotinate (3.9 g, 17 mmol) in THF (50 mL) was treated with LiAlH4 (3.6 g, 95 mmol), allowed to warm to 0° C. and stirred for 1 h. The mixture was quenched with 10% NaOH (3.6 mL), filtered and the filtrate treated with water and extracted with EtOAc (3×). The combined organics were washed with brine, dried (MgSO4) and concentrated in vacuo to provide (6-chloro-4-(ethylamino)pyridin-3-yl)methanol (2.5 g, 79% yield). 1H NMR (400 MHz, DMSO-d6): δ 7.84 (s, 1H), 6.55 (s, 1H), 6.17 (m, 1H), 5.25 (t, J=5.2 Hz, 1H), 4.44 (q, J=7.2 Hz, 2H), 3.23 (m, 2H), 1.23 (t, J=7.2 Hz, 3H).
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[C:7]1([OH:13])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.F[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[N+:22]([O-:24])=[O:23].O>C1COCC1.C(OCC)(=O)C>[F:21][C:18]1[CH:19]=[CH:20][C:15]([O:13][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:16]([N+:22]([O-:24])=[O:23])[CH:17]=1
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1cc(F)ccc1Oc1ccccc1
Temperature: 40 °C
Reaction time: 0.25 h
Yield: 85.9 %

Procedure:
Cs2CO3 (12.1 g, 62.9 mmol) was added to a solution of phenol (5.9 g, 62.9 mmol) in 400 mL of THF under N2. After stirring for 15 min. 2,5-difluoronitrobenzene (6.82 mL, 62.9 mmol) in 50 mL of THF was added. The resulting mixture was heated to 40° C. for 25 h. Reaction was followed by HPLC to detect disappearance of 2,5-difluoronitrobenzene. Water and ethyl acetate were added, followed by extraction with ethyl acetate (2×). The combined organic layers were successively washed with saturated aq. sodium bicarbonate (3×), water and brine, dried (Na2SO4) and evaporated. The crude compound was chromatographed on silica to remove excess of phenol. Elution with toluene/ethyl acetate 95:5 gave the title compound (12.6 g, 86%). Data: (m/z)=234 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.Cl.[CH3:13][O:14][C:15](=[O:19])[C@@H:16]([CH3:18])[NH2:17].C(=O)([O-])[O-].[K+].[K+]>CCOCC.O>[Cl:1][C:2]1[N:7]=[C:6]([NH:17][C@@H:16]([C:15]([O:14][CH3:13])=[O:19])[CH3:18])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: COC(=O)[C@@H](C)N
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: COC(=O)[C@@H](C)Nc1nc(Cl)ncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 17.9 %

Procedure:
To a stirred solution of 2,4-dichloro-5-nitropyrimidine (17.5 g, 90 mmol) in ether (100 mL) at —OC was added a solution of D-alanine methyl ester hydrochloride (12 g, 85.96 mmol) in water (50 mL). To the resulting mixture was added potassium carbonate (71.2 g, 515.5 mmol) in portions with vigorous stirring. Then the reaction was allowed to warm up to rt and stirred for 16 h. The precipitated solid was filtered to afford desired product as yellow solid (4 g). Ether layer was separated from filtrate, the aqueous layer was extracted with ether (50 mL×3). Combined ether layers were dried (Na2SO4), evaporated to give a crude residue, which was then purified by silica gel flash chromatography to give another 2.7 g of desired product. 1HNMR (300 MHz, CDCl3): δ 1.61 (d, J=7.2 Hz, 3H), 3.82 (s, 3H), 4.90-5.0 (m, 1H), 8.75 (br s 1H) and 9.07 (s, 1H).
Reaction SMILES: C[Li].[CH2:3]([N:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)C1C(OCC)=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:25](=O)=O.[CH3:28][C:29]([CH3:31])=[O:30].O>C(OCC)C.C1COCC1>[CH2:3]([N:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:28]1[C:29]([OH:30])([CH3:25])[CH3:31])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(=O)C1c2ccccc2CCN1Cc1ccccc1
Reactant: O=C=O
Reactant: CC(C)=O
Agent: [Li]C
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(O)C1c2ccccc2CCN1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In a dry ice-acetone bath under an argon atmosphere, a solution of 1.0 M methyllithium in diethyl ether (16.2 mL) was added dropwise to a solution of ethyl 2-benzyl-1,2,3,4-tetrahydroisoquinoline-1-carboxylate (1.99 g) in THF (20 mL) over 15 minutes. The reaction liquid was stirred in a dry ice-acetone bath for 0.5 hours and then further stirred in an ice bath for 1 hour. The reaction liquid was cooled again in the dry ice-acetone bath, and a solution of 1.04 M methyllithium in diethyl ether (3.24 mL) was added thereto. The reaction liquid was stirred in the dry ice-acetone bath for 0.5 hours and then stirred in the ice bath for 1 hour. Water was added to the reaction liquid, followed by extraction with EtOAc. The extract was washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-EtOAc) to obtain 2-(2-benzyl-1,2,3,4-tetrahydroisoquinolin-1-yl)propan-2-ol (1.27 g).
Reaction SMILES: [CH3:1][Li].[CH:3]1([C:9]2[CH:10]=[N:11][O:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:22])[CH3:21])=[CH:16][CH:15]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1>C1COCC1>[CH:3]1([C:9]2[CH:10]=[N:11][O:12][C:13]=2[C:14]2[CH:15]=[CH:16][C:17]([C:20]([OH:22])([CH3:1])[CH3:21])=[CH:18][CH:19]=2)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: [Li]C
Reactant: CC(=O)c1ccc(-c2oncc2C2CCCCC2)cc1
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc(-c2oncc2C2CCCCC2)cc1
Reaction time: 0.25 h

Procedure:
Methyl lithium (159 μL, 1.6 M solution in Et2O, 0.25 mmol) was added dropwise to a solution of 1-(4-(4-cyclohexylisoxazol-5-yl)phenyl)ethanone obtained above (57 mg, 0.21 mmol) in THF (2 mL) at 0° C. After stirring for 15 min, another 100μL of the methyl lithium solution was added to the reaction mixture. After being stirred for an additional 1 h at 0° C., the mixture was quenched with saturated aqueous NH4Cl and diluted with EtOAc. The aqueous layer was extracted with EtOAc, and the combined organic layers were washed with NaCl, dried with magnesium sulfate, filtered and concentrated in vacuo to give a yellow oil. The crude material was purified by flash column chromatography (20%→40% EtOAc/hexanes) to afford 2-(4-(4-cyclohexylisoxazol-5-yl)phenyl)propan-2-ol as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 8.23 (s, 1H), 7.62 (m, 4H), 2.77 (m, 1H), 2.09 (m, 1H), 1.86 (m, 5H), 1.63 (s, 6H), 1.37 (m, 5H).
Reaction SMILES: [CH3:1][C@:2]1([NH:21][C:22]2[CH:27]=[N:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][N:23]=2)[CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:7][C:8]([C:10]1[C:15]([N:16]2[N:20]=[CH:19][CH:18]=[N:17]2)=[CH:14][CH:13]=[CH:12]N=1)=[O:9].[CH3:32][C@]1(NC2C=NC(C(F)(F)F)=CN=2)CCC[C@@H]1N.N1N(C2C=CC=CC=2C(O)=O)N=CC=1>>[CH3:1][C@:2]1([NH:21][C:22]2[CH:27]=[N:26][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:24][N:23]=2)[CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:7][C:8](=[O:9])[C:10]1[CH:32]=[CH:12][CH:13]=[CH:14][C:15]=1[N:16]1[N:20]=[CH:19][CH:18]=[N:17]1
Reactant: C[C@]1(Nc2cnc(C(F)(F)F)cn2)CCC[C@@H]1NC(=O)c1ncccc1-n1nccn1
Reactant: C[C@]1(Nc2cnc(C(F)(F)F)cn2)CCC[C@@H]1N
Agent: O=C(O)c1ccccc1-n1nccn1
Product: C[C@]1(Nc2cnc(C(F)(F)F)cn2)CCC[C@@H]1NC(=O)c1ccccc1-n1nccn1

Procedure:
Prepared according to the procedure for N-[(1S,2S)-2-methyl-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]-3-(2H-1,2,3-triazol-2-yl)pyridine-2-carboxamide (Example 77) from (1S,2S)-1-methyl-1-N-[5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine (Intermediate 25; 510 mg, 1.96 mmol) and 2-(2H-1,2,3-triazol-2-yl)benzoic acid (CAS number 1001401-62-2; 445 mg, 2.35 mmol) except this was then partitioned between water (20 ml) and DCM (10 ml). The organics were washed with water (2×20 ml) and brine (20 ml), filtered through a hydrophobic frit and concentrated in vacuo. The residue was purified by column chromatography (silica, 0-100% ethyl acetate/petrol) followed by a trituration with diethyl ether and recrystallised from IPA/water to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([Cl:11])[CH:3]=1.[N:12]([O-])=O.[Na+].[Sn](Cl)Cl>Cl.O>[ClH:11].[Cl:11][C:4]1[CH:3]=[C:2]([NH:1][NH2:12])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: Nc1ccc(C(=O)O)c(Cl)c1
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: NNc1ccc(C(=O)O)c(Cl)c1
Temperature: 0 °C

Procedure:
To a suspension of 4-amino-2-chlorobenzoic acid (3.00 g, 17.5 mmol) in hydrochloric acid (1.0 M, 30 mL) at 0° C. was added a solution of sodium nitrite (1.24 g, 18.0 mmol) in water (5.0 mL) over 5 min and the reaction mixture maintained at 0° C. for 5 hr. The resulting mixture was treated with tin(II) chloride (9.28 g, 49.0 mmol) in hydrochloric acid (1.0 M, 60 mL) and was warmed to RT for 64 hr. The resulting thick precipitate which formed was isolated by filtration, washed with ethanol (16 mL) and ether (15 mL) and was dried in vacuo to afford 2-chloro-4-hydrazinylbenzoic acid hydrochloride as a beige solid (3.54 g, 90% purity, 82%); Rt 0.22 min (Method 2); m/z 187 (M+H)+, (ES+). This material was used in the subsequent step without further purification.