Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[C:4]1[CH:34]=[CH:33][C:7]([C:8]([NH:10][CH:11]2[CH2:16][CH2:15][CH:14]([O:17][C:18](=[O:20])[CH3:19])[CH2:13][CH:12]2[C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH:30]([F:32])[F:31])[CH:22]=2)=O)=[CH:6][CH:5]=1.[OH-].[Na+]>P(Cl)(Cl)(Cl)=O.ClCCl>[CH3:1][O:2][C:3](=[O:35])[C:4]1[CH:34]=[CH:33][C:7]([C:8]2[C:26]3[C:21](=[CH:22][C:23]([O:29][CH:30]([F:32])[F:31])=[C:24]([O:27][CH3:28])[CH:25]=3)[CH:12]3[CH:11]([CH2:16][CH2:15][CH:14]([O:17][C:18](=[O:20])[CH3:19])[CH2:13]3)[N:10]=2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(C(=O)NC2CCC(OC(C)=O)CC2c2ccc(OC)c(OC(F)F)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1ccc(C2=NC3CCC(OC(C)=O)CC3c3cc(OC(F)F)c(OC)cc32)cc1
Temperature: 100 °C
Yield: 64.4 %

Procedure:
500 mg of N-{(1RS,2RS,4RS)-4-acetoxy-2-[3-(1,1-difluoro-methoxy)-4-methoxy-phenyl]-cyclohexyl}-terephthalamic acid methyl ester (compound D2) are dissolved in 2 ml of phosphorus oxychloride and heated for 4.5 h at 100° C. After cooling to room temperature the sample is diluted with 10 ml of dichloromethane and added dropwise to an aqueous sodium hydroxide solution. The water layer is extracted twice with dichloromethane. The solvent is removed and the crude product purified by chromatography on silica gel to give 310 mg of the title compound as a colourless foam.
Reaction SMILES: [BH4-].[Li+].C[Si](C)(C)Cl.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[CH:16][N+:17]([O-])=O)=[CH:11][C:10]=1[F:20].CO>C1COCC1>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH2:17])=[CH:11][C:10]=1[F:20]
Reactant: O=[N+]([O-])C=Cc1ccc(Cl)c(F)c1
Agent: C[Si](C)(C)Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: NCCc1ccc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 72 %

Procedure:
Lithium borohydride (2.16 g, 99 mmol) was suspended in THF (50 ml). Trimethylchlorosilane (21.6 g, 198 mmol) was added dropwise. A solution of 1-chloro-2-fluoro-4-(2-nitro-vinyl)-benzene (5.0 g, 24.8 mmol) in THF (20 ml) was added dropwise. Strong gas evolution and foam formation was observed. The white suspension was stirred at RT for 3 days. Carefully MeOH (80 ml) was added. The solvents were removed in vacuo and the residue was purified by flash column chromatography (CH2Cl2/MeOH+5% aq. NH4OH 4:1) to yield 2-(4-chloro-3-fluoro-phenyl)-ethylamine (3.1 g, 73%) as a white solid. MS (ISP) 174.1 (M+H)+. 1HNMR (DMSO-d, 300 MHz): δ 2.92 (t, J=4.8 Hz, 2H), 3.02 (t, J=6.3 Hz, 2H), 7.15 (dd, J=6.0 and 1.2 Hz, 1H), 7.38 (dd, J=1.2 and 7.8 Hz), 7.53 (t, J=6.3 Hz, 1H), 7.93 (br, 2H).
Reaction SMILES: [Cl:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8](Cl)=[O:9])(=[O:4])=[O:3].[CH:14]([O:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1)([CH3:16])[CH3:15]>C1(C)C=CC=CC=1>[CH:14]([O:17][C:18]1[CH:24]=[CH:23][C:21]([NH:22][C:8]([C:7]2[CH:6]=[C:5]([S:2]([Cl:1])(=[O:4])=[O:3])[CH:13]=[CH:12][CH:11]=2)=[O:9])=[CH:20][CH:19]=1)([CH3:16])[CH3:15]
Reactant: O=C(Cl)c1cccc(S(=O)(=O)Cl)c1
Reactant: CC(C)Oc1ccc(N)cc1
Solvent: Cc1ccccc1
Product: CC(C)Oc1ccc(NC(=O)c2cccc(S(=O)(=O)Cl)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.7 %

Procedure:
3-(Chlorosulfonyl)benzoyl chloride (5.00 g) was added to a toluene (50 mL) solution of 4-isopropoxyaniline (3.17 g), and stirred overnight at room temperature. The solid in the reaction system was removed through filtration, and the filtrate was evaporated under reduced pressure. The residue was purified through silica gel column chromatography (ethyl acetate/hexane=from 0% to 100%, gradient), then the resulting compound was suspended in diisopropyl ether added thereto, and the solid was collected through filtration to give the entitled compound (2.27 g, 35%) as a pale blue solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[NH:12][NH2:13].C(Cl)Cl.[CH3:17][OH:18]>>[CH2:2]([C:3]1[NH:12][C:17](=[O:18])[N:12]([C:3]2[CH:4]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:10]=[CH:11][C:2]=2[Cl:1])[N:13]=1)[CH2:11][CH2:10][CH3:5]
Reactant: COC(=O)c1ccc(Cl)c(NN)c1
Reactant: CO
Solvent: ClCCl
Product: CCCCc1nn(-c2cc(C(=O)OC)ccc2Cl)c(=O)[nH]1
Yield: 37 %

Procedure:
By the procedure of Example 3, Step C, the title compound was prepared from methyl 4-chloro-3-hydrazinobenzoate (from Step B) in 37% yield as an orange gum (TLC in 95:5 CH2Cl2 --MeOH), mass spectrum (FAB) m/e 310 (M+1)+.
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([O:10][CH2:11][CH:12]2[O:14][CH2:13]2)[CH2:4][C:3]1([CH3:16])[CH3:15].[NH:17]([CH2:21][CH2:22][OH:23])[CH2:18][CH2:19][OH:20]>O>[OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([O:10][CH2:11][CH:12]([OH:14])[CH2:13][N:17]([CH2:21][CH2:22][OH:23])[CH2:18][CH2:19][OH:20])[CH2:4][C:3]1([CH3:16])[CH3:15]
Reactant: OCCNCCO
Reactant: CC1(C)CC(OCC2CO2)CC(C)(C)N1O
Solvent: O
Product: CC1(C)CC(OCC(O)CN(CCO)CCO)CC(C)(C)N1O
Yield: 29.9 %

Procedure:
A solution of 2.28 g (0.01 mol) of 1-oxyl-2,2,6,6-tetramethyl-4-glycidyloxypiperidine and 1.05 g (0.01 mol) of diethanolamine in 25 mL of water is stirred at ambient temperature for 16 hours. The solution is then extracted with methylene chloride. The methylene chloride extract is dried over anhydrous magnesium sulfate, filter and concentrated. The crude reaction product is purified by column chromatography to afford 1.0 g of the title compound as a red oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][C@H:12]([C:15](NC(C)C)=[O:16])[CH2:11][CH2:10]2)[C:5]([N+:21]([O-:23])=[O:22])=[CH:4][N:3]=1.N[C@@H]1CC[C@H](C(O)=[O:32])CC1>>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C@@H:9]2[CH2:10][CH2:11][C@H:12]([C:15]([OH:16])=[O:32])[CH2:13][CH2:14]2)[C:5]([N+:21]([O-:23])=[O:22])=[CH:4][N:3]=1
Reactant: N[C@H]1CC[C@@H](C(=O)O)CC1
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](Nc2cc(Cl)ncc2[N+](=O)[O-])CC1
Product: O=C(O)[C@H]1CC[C@@H](Nc2cc(Cl)ncc2[N+](=O)[O-])CC1

Procedure:
The compound was made using a procedure analogous to that used in the preparation of cis-4-(2-chloro-5-nitropyridin-4-ylamino)-N-isopropylcyclohexanecarboxamide using cis-4-aminocyclohexanecarboxylic acid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[N+:21]([O-])=O.[ClH:24]>C(O)C.[Pd]>[ClH:24].[ClH:24].[NH2:21][C:3]1[CH:4]=[CH:5][C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])[CH2:9]2)=[N:7][C:2]=1[NH2:1]
Reactant: Nc1nc(N2CCC[C@@H](C(=O)N3CCCC3)C2)ccc1[N+](=O)[O-]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Nc1ccc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
Into a Parr bottle was added 10% palladium-on-carbon (50% wet, 1487.2 mg) followed by ethanol (10 mL) which was previously bubbled with nitrogen and cooled to 0° C. with an ice-water bath. (R)-(1-(6-Amino-5-nitropyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone (10.612 g, 33.228 mmol) in ethanol (84 mL) was added into the Parr bottle followed by concentrated hydrochloric acid (8.59 mL, 99.6 mmol) dissolved in ethanol (10 mL) under a nitrogen atmosphere. The reaction mixture was purged with nitrogen and evacuated 3 times. The mixture was submitted to a hydrogen atmosphere (45 PSI). A drop in pressure was observed and it was increased to 46 PSI. This process was repeated several times over a period of 30 minutes. The reaction mixture was shaken for a total of 1 h. Then it was filtered through Celite and the residue was rinsed with ethanol (1 L). The solvent was removed under reduced pressure and the residue was redissolved in methanol. The solvent was removed under reduced pressure and the solid was dried under high vacuum to afford the title compound (12.0 g). The material was used without further purification. 1H NMR (400 MHz, CD3OD) δ 1.67-1.81 (m, 2H) 1.83-2.10 (m, 6H) 2.85-2.95 (m, 1H) 3.32-3.55 (m, 5H) 3.66 (dt, 1H) 3.89 (d, 1H) 3.97 (dd, 1H) 6.38 (d, 1H) 7.64 (d, 1H); MS (ES+) (M+H) 290.2.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:16][C:9]2[NH:10][C:11](=[O:15])[C:12](=[O:14])[NH:13][C:8]=2[C:7]=1[CH2:17][CH3:18])=[O:5])C.[OH-].[Na+].Cl.O>O1CCCC1>[C:4]([C:6]1[S:16][C:9]2[NH:10][C:11](=[O:15])[C:12](=[O:14])[NH:13][C:8]=2[C:7]=1[CH2:17][CH3:18])([OH:5])=[O:3]
Reactant: CCOC(=O)c1sc2[nH]c(=O)c(=O)[nH]c2c1CC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCc1c(C(=O)O)sc2[nH]c(=O)c(=O)[nH]c12
Temperature: 0 °C
Yield: 65 %

Procedure:
A mixture of 6-ethoxycarbonyl-7-ethylthieno[2,3-b]-pyrazine-2,3(1H,4H)-dione (24.5 g, 91 mmol) and sodium hydroxide (10.96 g, 274 mmol) in 50% aqueous tetrahydrofuran (340 ml) was heated at 50°-60° C. for 16 h. The reaction mixture was cooled to 0° C. and acidified (pH=2) with hydrochloric acid. Water (300 ml) was added, the precipitate filtered off, washed with water and dried. Purification was performed by dissolving in 2 M sodium hydroxide solution, extraction with dichloromethane and precipitation of the aqueous phase with hydrochloric acid. The precipitate was filtered off, washed with water and dried to afford 14.2 g (65%) of the title compound. M.p. 230°-232° C. 1H-NMR (DMSO-d6, δ) : 1. 09 (t, 3H) 3.03 (q, 2H), 11.90 (s, 1H), 12.50 (br. s, 1H), 12.92 (br. s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[CH:4]([NH:16][C:17](=[O:36])[CH:18]([NH:23][S:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N+:33]([O-:35])=[O:34])(=[O:26])=[O:25])[CH2:19][CH:20]1[CH2:22][CH2:21]1)[CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1.Br[CH2:39][CH2:40]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:37])[CH:4]([N:16]1[CH2:40][CH2:39][N:23]([S:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[N+:33]([O-:35])=[O:34])(=[O:25])=[O:26])[CH:18]([CH2:19][CH:20]2[CH2:21][CH2:22]2)[C:17]1=[O:36])[CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1
Reactant: COC(=O)C(Cc1ccc2ccccc2c1)NC(=O)C(CC1CC1)NS(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(Cc1ccc2ccccc2c1)N1CCN(S(=O)(=O)c2ccccc2[N+](=O)[O-])C(CC2CC2)C1=O
Temperature: 65 °C
Reaction time: 15 h
Yield: 98 %

Procedure:
To a solution of 2-[3-cyclopropyl-2-(2-nitro-benzenesulfonylamino)-propionylamino]-3-naphthalen-2-yl-propionic acid methyl ester, 12, (3.46 g, 6.59 mmol) and 1,2-dibromoethane (12.38 g, 65.9 mmol) in DMF (40 mL) is added potassium carbonate (9.10 g, 65.8 mmol). The reaction mixture is stirred for 15 hours at 65° C., cooled and quenched with aqueous NH4Cl solution. The mixture is then extracted several times with EtOAc and the combined extracts dried over Na2SO4 and concentrated in vacuo. The resulting residue is purified over silica gel (hexanes/EtOAc, 1:2) to afford 3.57 g (98% yield) of the desired product. 1H NMR (300 MHz, CD3OD) δ 8.01–8.08 (m, 1H), 7.58–7.84 (m, 7H), 7.43–7.52 (m, 2H), 7.35 (dd, J=8.4 Hz, 1H), 5.38 (dd, J=11.7, 4.8 Hz, 1H), 4.33–4.44 (m, 1H), 3.76–3.88 (m, 1H), 3.69 (s, 3H), 3.21–3.66 (m, 4H), 2.99–3.14 (m, 1H), 1.40–1.53 (m, 1H), 1.02–1.16 (m, 1H), −0.14–−0.02 (m, 3H), −0.34–−0.20 (m, 2H); MS (ESMS) m/z 552.2 (M+H)+.
Reaction SMILES: C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.Br[C:48]1[CH:49]=[C:50]2[C:56]3([CH2:61][CH2:60][N:59]([C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])[CH2:58][CH2:57]3)[CH2:55][N:54]([C:69]3[C:70]4[C@H:77]([CH3:78])[CH2:76][CH2:75][C:71]=4[N:72]=[CH:73][N:74]=3)[C:51]2=[CH:52][CH:53]=1.[Cl:79][C:80]1[CH:81]=[C:82]([NH2:86])[CH:83]=[CH:84][CH:85]=1.C1(C)C=CC=CC=1>CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:79][C:80]1[CH:81]=[C:82]([NH:86][C:48]2[CH:49]=[C:50]3[C:56]4([CH2:61][CH2:60][N:59]([C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])[CH2:58][CH2:57]4)[CH2:55][N:54]([C:69]4[C:70]5[C@H:77]([CH3:78])[CH2:76][CH2:75][C:71]=5[N:72]=[CH:73][N:74]=4)[C:51]3=[CH:52][CH:53]=2)[CH:83]=[CH:84][CH:85]=1
Reactant: C[C@@H]1CCc2ncnc(N3CC4(CCN(C(=O)OC(C)(C)C)CC4)c4cc(Br)ccc43)c21
Reactant: Nc1cccc(Cl)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C[C@@H]1CCc2ncnc(N3CC4(CCN(C(=O)OC(C)(C)C)CC4)c4cc(Nc5cccc(Cl)c5)ccc43)c21
Temperature: 95 °C
Yield: 59.5 %

Procedure:
A pear-shaped flask was charged with Pd(OAc)2 (0.9 mg, 0.004 mmol) and rac-BINAP (81 mg, 0.13 mmol) and purged with N2. To the flask was added (R)-tert-butyl 5-bromo-1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate (20 mg, 0.040 mmol), 3-chlorobenzenamine (10 mg, 0.080 mmol), NaOBut (7.7 mg, 0.080 mmol) and toluene (0.5 mL). The mixture was heated at about 95° C. for 2 days. After cooling to about room temperature, the reaction was diluted with EtOAc, filtered through Celite, and concentrated. The crude product was purified by column chromatography (DCM:MeOH, 80:1) to give (R)-tert-butyl 5-(3-chlorophenylamino)-1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate (13 mg, 59%) as a yellow oil. LCMS (APCI+) m/z 546 [M+H]+; Rt=4.24 min.
Reaction SMILES: [CH2:1]([C@@H:3]([CH2:6][CH2:7][CH3:8])[CH2:4][OH:5])[CH3:2].CCN(CC)CC.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C(Cl)Cl>[CH2:1]([C@@H:3]([CH2:6][CH2:7][CH3:8])[CH2:4][O:5][S:17]([CH3:16])(=[O:19])=[O:18])[CH3:2]
Reactant: CCC[C@H](CC)CO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC[C@H](CC)COS(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a −10° C. stirred solution of (S)-2-ethyl-pentan-1-ol (1.30 g, 11.2 mmol) in dry CH2Cl2 (35 mL) was added Et3N (2.33 mL, 16.8 mmol). The reaction was stirred at this temperature for 15 minutes and methansulfonyl chloride (0.952 mL, 12.3 mmol) was added. The reaction was allowed to warm to room temperature overnight with good stirring. The reaction was washed with 1N HCl (3×30 mL), sat. NaHCO3 (3×30 mL), and brine (2×30 mL). The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure to give a quantitative yield of crude product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9](O)[CH2:10][CH3:11])[CH:6]=[CH:7][CH:8]=1.[ClH:13]>>[Cl:13][CH:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[CH2:10][CH3:11]
Reactant: CCC(O)c1cccc(OC)c1
Reactant: Cl
Product: CCC(Cl)c1cccc(OC)c1

Procedure:
The preparation was effected in analogy to example 1(b) from 1-(3'-methoxyphenyl)-propan-1-ol and HCl gas.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=2[CH3:17])[C:11]([OH:13])=O)=[C:5]([CH3:7])[N:6]=1.Cl.[NH:19]1[CH2:22][CH:21]([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=2)[CH2:20]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][C:2]1[NH:3][C:4]([C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=2[CH3:17])[C:11]([N:19]2[CH2:22][CH:21]([C:23]3[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=3)[CH2:20]2)=[O:13])=[C:5]([CH3:7])[N:6]=1
Reactant: Cc1nc(C)c(-c2cc(C(=O)O)ccc2C)[nH]1
Reactant: N#Cc1ccc(C2CNC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(C)c(-c2cc(C(=O)N3CC(c4ccc(C#N)cc4)C3)ccc2C)[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 45 %

Procedure:
To a mixture of 3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 5.7, 0.484 g, 2.10 mmol), 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2, 0.41 g, 2.10 mmol), HOBT (0.085 g, 7.40 mmol) and EDCI (0.603 g, 3.15 mmol) in DMF (8 mL) was added DIEA (1.09 mL, 6.3 mmol). The mixture was stirred at room temperature for 16 hours, then partitioned between EtOAc (300 mL) and water (30 mL). The organic layer was washed with brine (3×30 mL) and the combined aqueous phases were back extracted with EtOAc (2×50 mL). All organic extracts were combined, dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc to 5% MeOH in EtOAc) to yield the title compound as a white solid (0.35 g, 45%). m/z (ES+) 371 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 7.66 (d with fine str., J=8.4 Hz, 2H), 7.54-7.48 (m, 2H), 7.44 (d with fine str., J=8.2 Hz, 2H), 7.30 (d, J=7.9 Hz, 1H), 4.77-4.56 (m, 2H), 4.35-4.18 (m, 2H), 3.97-3.87 (m, 1H), 2.38 (s, 3H), 2.30 (s, 3H), 2.10 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:17]2[C:22](=[O:23])[NH:21][C:20](=[O:24])[CH:19]=[N:18]2)[CH:5]=[CH:6][C:7]=1[CH:8](Cl)[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1.[SH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1.N12CCCN=C1CCCCC2.[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N:17]2[C:22](=[O:23])[NH:21][C:20](=[O:24])[CH:19]=[N:18]2)[CH:5]=[CH:6][C:7]=1[CH:8]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)[S:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1
Reactant: O=c1cnn(-c2ccc(C(Cl)c3ccc(Cl)cc3)c(Cl)c2)c(=O)[nH]1
Reactant: Sc1ccccn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: O=c1cnn(-c2ccc(C(Sc3ccccn3)c3ccc(Cl)cc3)c(Cl)c2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.4 %

Procedure:
A mixture of 2-[3-chloro-4-[chloro(4-chlorophenyl)methyl]phenyl]-1,2,4-triazine-3,5(2H,4H)-dione (0.015 mol) and 2-mercaptopyridine (0.04 mol) in THF (100 ml) was stirred overnight at RT. 1,8-diazabicyclo[5.4.0]undec-7-ene (0.03 mol) was added and the resulting reaction mixture was stirred for 3 hours. NaOH (1 N; 50 ml) was added. The mixture was stirred for 5 minutes, then extracted with EtOAc. The separated organic layer was washed with water, dried, filtered and the solvent evaporated. The aqueous layers were combined, then acidified (pH=6) with HCl (1 N). This mixture was extracted with CH2Cl2. The separated organic layer was dried, filtered, and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/THF/CH3OH 94/5/1). The pure fractions were collected and the solvent was evaporated. The residue was stirred overnight in diethyl ether. The solvent was evaporated. The residue was dried, yielding 2.98 g (43%) (±)-2-[3-chloro-4-[(4-chlorophenyl)(2-pyridinyl-thio)methyl]phenyl]-1,2,4-triazine-3,5(2H,4H)-dione (compound 93).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([N:18]3[CH2:23][C@H:22]([CH3:24])[NH:21][C@H:20]([CH3:25])[CH2:19]3)[CH:15]=[CH:14][C:13]=2[O:26][CH3:27])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:28][O:29][CH2:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1.CC(C)([O-])C.[K+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:25][C@H:20]1[NH:21][C@@H:22]([CH3:24])[CH2:23][N:18]([C:16]2[CH:15]=[CH:14][C:13]([O:26][CH3:27])=[C:12]([NH:11][S:8]([C:5]3[CH:6]=[CH:7][C:2]([C:35]4[CH:34]=[CH:33][CH:32]=[C:31]([CH2:30][O:29][CH3:28])[CH:36]=4)=[CH:3][CH:4]=3)(=[O:10])=[O:9])[CH:17]=2)[CH2:19]1
Reactant: COCc1cccc(B(O)O)c1
Reactant: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: COCc1cccc(-c2ccc(S(=O)(=O)Nc3cc(N4C[C@@H](C)N[C@@H](C)C4)ccc3OC)cc2)c1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 4-bromo-N-[5-(cis-3,5-dimethyl-1-piperazinyl)-2-(methyloxy)phenyl]benzenesulfonamide (E106) (100 mg, 0.22 mmol) and {3-[(methyloxy)methyl]phenyl}boronic acid (75 mg, 0.45 mmol) in DME (3 ml) was added potassium tert-butoxide (220 mg, 1.96 mmol) and tetrakis(triphenylphosphine)palladium(0) (15 mg, 0.01 mmol) in water (1 ml) and the resulting mixture stirred in a microwave (set at high absorbance) at 100° C. for 30 minutes. The resulting mixture was then evaporated and purified by SCX followed by mass directed autoprep HPLC to afford the title compound (E117). MS (ES+) m/e 496 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([C:11]3[CH:12]=[CH:13][C:14](O)=[N:15][CH:16]=3)[NH:8][C:5]2=[N:6][CH:7]=1.P(Cl)(Cl)([Cl:20])=O>>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[N:15][C:14]([Cl:20])=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ccc(-c2nc3cc(Br)cnc3[nH]2)cn1
Product: Clc1ccc(-c2nc3cc(Br)cnc3[nH]2)cn1
Temperature: 110 °C
Reaction time: 4 h

Procedure:
5-(6-Bromo-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-ol (300 mg, 1.03 mmol) was added to phosphorous oxychloride (6 ml) and the mixture was stirred at 110° C. for 4 h. The excess phosphorous oxychloride was evaporated off and the remaining oil was purified by flash chromatography using ethyl acetate/heptane as eluent. The title compound was isolated as a yellow solid (139 mg, 44%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Cl:13]S(O)(=O)=O.OS(O)(=O)=O.O=S(=O)=O.II>>[F:1][C:2]1[C:10]([Cl:13])=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=S(=O)(O)Cl
Reactant: O=C(O)c1cc(F)c(F)cc1F
Agent: II
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Product: O=C(O)c1cc(F)c(F)c(Cl)c1F

Procedure:
the chlorination of the 2,4,5-trifluorobenzoic acid is carried out in the melt, under pressure and/or in a solvent, for example chlorosulphonic acid or oleum, in the presence of halogen transfer agents, for example iodine. 2,4,5-Trifluoro-3-chlorobenzoic acid is obtained in this reaction. However, since the reaction mixture still contains unchanged starting material and some 2,4,5-trifluoro-3,6-dichlorobenzoic acid, the crude mixture is treated, without intermediate isolation, with thionyl chloride. The desired 2,4,5-rifluoro-3-chlorobenzoyl chloride is then obtained by fractional distillation. However, it is more favorable to carry out the separation by distillation of the acid fluorides.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[NH2:12][C:13]1[N:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21]([N:23]([CH3:35])[CH2:24][C:25]2[N:26]([CH3:34])[C:27]3[C:32]([CH:33]=2)=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:22])=[CH:15][CH:14]=1.C(=O)(O)[O-].[Na+]>C1COCC1>[C:4]([C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[C:1]([NH:12][C:13]1[N:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21]([N:23]([CH3:35])[CH2:24][C:25]2[N:26]([CH3:34])[C:27]3[C:32]([CH:33]=2)=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:22])=[CH:15][CH:14]=1)=[O:11])([OH:6])=[O:5]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CN(Cc1cc2ccccc2n1C)C(=O)/C=C/c1ccc(N)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(Cc1cc2ccccc2n1C)C(=O)/C=C/c1ccc(NC(=O)c2ccccc2C(=O)O)nc1
Reaction time: 48 h
Yield: 15.6 %

Procedure:
Phthalic anhydride (0.81 g, 5.48 mmole) was added to a solution of (E)-3-(6-aminopyridin-3-yl)-N-methyl-N-(1-methyl-1H-indol-2-ylmethyl)acrylamide (0.44 g, 1.37 mmole) and sodium bicarbonate (0.58 g, 6.85 mmole) in THF (70 mL) at RT, and the reaction was heated at reflux under nitrogen. After 48 hr, the reaction was concentrated in vacuo and the residue was diluted with water and extracted with ethyl acetate. The combined extracts were dried over Na2SO4 and concentrated. Flash chromatography on silica gel (10% MeOH/CHCl3) gave the title compound (0.10 g, 16%) as a light yellow solid: MS (ES) m/e 469 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[N:10]=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[F:20][C:21]([F:34])([F:33])[O:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:19][S:29]([C:26]2[CH:25]=[CH:24][C:23]([O:22][C:21]([F:20])([F:33])[F:34])=[CH:28][CH:27]=2)(=[O:31])=[O:30])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[N:10]=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Reactant: Nc1cnc(Oc2cc3ccccc3cn2)c(Cl)c1
Product: O=S(=O)(Nc1cnc(Oc2cc3ccccc3cn2)c(Cl)c1)c1ccc(OC(F)(F)F)cc1

Procedure:
The title compound was prepared by reacting 5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-amine (obtained as per procedure described in preparation 2) and 4-(trifluoromethoxy)benzene-1-sulfonyl chloride.