Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[C:13]([O:15][CH2:16][CH3:17])[NH:14][C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[NH3:18]>CO>[CH2:16]([O:15][C:13]1[NH:14][C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:18])[C:11]=2[N:12]=1)[CH3:17]
Reactant: N
Reactant: CCOc1nc2c(Cl)nc3ccccc3c2[nH]1
Solvent: CO
Product: CCOc1nc2c(N)nc3ccccc3c2[nH]1
Temperature: 150 °C

Procedure:
4-Chloro-2-ethoxy-1H-imidazo[4,5-c]quinoline (500 mg) was added to a high-pressure vessel with ammonia (40 mL of a 7 N solution in methanol), and the vessel was sealed and heated at 150° C. overnight. An analysis by LC/MS indicated the presence of starting material, and the reaction was heated at 150° C. for an additional four hours, allowed to cool, and concentrated under reduced pressure. The crude product was purified twice by automated flash chromatography (silica cartridge, eluting with aqueous ammonium hydroxide:methanol:dichloromethane in a gradient from 0:0:100 to 0.4:7.6:92) to provide 52 mg of 2-ethoxy-1H-imidazo[4,5-c]quinolin-4-amine as a white solid.
Reaction SMILES: [CH2:1]([C:3]([CH3:9])([CH2:7][CH3:8])[C:4](O)=O)[CH3:2].[NH2:10][NH:11][C:12]([NH2:14])=[S:13].P(Cl)(Cl)(Cl)=O.[OH-].[NH4+]>O1CCOCC1>[NH2:14][C:12]1[S:13][C:4]([C:3]([CH2:7][CH3:8])([CH3:9])[CH2:1][CH3:2])=[N:10][N:11]=1
Reactant: CCC(C)(CC)C(=O)O
Reactant: NNC(N)=S
Agent: [NH4+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O=P(Cl)(Cl)Cl
Product: CCC(C)(CC)c1nnc(N)s1
Temperature: 90 °C
Yield: 91.9 %

Procedure:
A solution containing 13.0 g of 2-ethyl-2-methylbutyric acid and 9.1 g of thiosemicarbazide in 125 ml of dioxane was stirred and heated to 90° C. To the stirred reaction mixture was added dropwise over thirty minutes 15.3 g of phosphorous oxychloride. Following complete addition, the reaction mixture was heated at 90° C. for six hours. The mixture was then cooled to about 30° C. and added to 100 g of ice. The aqueous mixture was made alkaline by the addition of ammonium hydroxide, and the alkaline solution was extracted several times with ethyl acetate. The extracts were combined, washed with water, dried, and the solvent was removed by evaporation under reduced pressure to afford 17.0 g of 2-amino-5-(1-ethyl-1-methylpropyl)-1,3,4-thiadiazole.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:4]=1[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[I-].[CH2:48]([N+:52]1[N:56]=[C:55]([CH3:57])[S:54][C:53]=1[CH3:58])[CH2:49][CH2:50][CH3:51]>>[CH2:48]([N:52]1[N:56]=[C:55]([CH3:57])[S:54]/[C:53]/1=[CH:58]\[C:5]([C:4]1[CH:8]=[C:9]([O:12][CH3:13])[CH:10]=[CH:11][C:3]=1[O:2][CH3:1])=[O:7])[CH2:49][CH2:50][CH3:51]
Reactant: COc1ccc(OC)c(C(=O)O)c1
Reactant: CCCC[n+]1nc(C)sc1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN1N=C(C)S/C1=C\C(=O)c1cc(OC)ccc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial 2,5-dimethoxybenzoic acid (0.9 mL of 0.2 M in DMA, 1.10 equiv) was added followed by the addition of HATU (76 mg in 0.7 mL of DMA, 0.2 mmol, 1.20 equiv.), DIEA (51 mg in 0.7 mL of DMA, 0.4 mmol, 2.40 equiv.), and finally 3-butyl-2,5-dimethyl-1,3,4-thiadiazol-3-ium iodide (49 mg in 0.7 mL of DMA, 0.17 mmol, 1 equiv.). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-D6/D2O) δ ppm 0.93 (t, 3 H) 1.30-1.36 (m, 2 H) 1.71-1.79 (m, 2 H) 2.47 (s, 3 H) 3.73 (s, 3 H) 3.80 (s, 3 H) 4.11 (t, 2 H) 6.59 (s, 1 H) 6.96-7.00 (m, 1 H) 7.02-7.06 (m, 1 H) 7.22 (d, 1 H); MS (ESI) m/z 335 (M+H)+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH2:11]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(Cl)Cl>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:21]2[CH2:22][CH2:23][N:18]([CH2:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:19][CH2:20]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Temperature: 25 °C

Procedure:
Reflux a mixture of 53.5 mL (0.504 mol) of 1-fluoro-4-nitrobenzene, 99.14 g(0.555 mol) of 1-benzylpiperazine, and 76.7 g (0.555 mol) potassium carbonate in acetonitrile for about 17 h. Cool the mixture to room temperature and dilute with methylene chloride and filter. Concentrate thefiltrate in vacuo. Dissolve the residue in methylene chloride and wash withwater. Dry the organic layer with anhydrous sodium sulfate and concentrate in vacuo to give the title compound. NMR (DMSO-d6): δ=2.59(t,4),3.42(t,4), 3.57(s,2), 6.80(d,2) 7.34(m,5) and 8.11(d,2) ppm.
Reaction SMILES: [NH2:1][C@@H:2]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH2:10][C@@H:9]([NH:14][C:15](=[O:29])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C@@H:24]3[CH2:28][CH2:27][CH2:26][O:25]3)=[CH:18][CH:17]=1)[CH2:8][CH2:7]2)[CH3:3].Br[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]Br.C(N(C(C)C)C(C)C)C>C(#N)C>[N:1]1([C@@H:2]([C:4]2[CH:5]=[C:6]3[C:11](=[CH:12][CH:13]=2)[CH2:10][C@@H:9]([NH:14][C:15](=[O:29])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C@@H:24]4[CH2:28][CH2:27][CH2:26][O:25]4)=[CH:18][CH:17]=2)[CH2:8][CH2:7]3)[CH3:3])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: C[C@@H](N)c1ccc2c(c1)CC[C@H](NC(=O)c1ccc(OC[C@@H]3CCCO3)cc1)C2
Reactant: BrCCCCCCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C[C@H](c1ccc2c(c1)CC[C@H](NC(=O)c1ccc(OC[C@@H]3CCCO3)cc1)C2)N1CCCCCC1
Temperature: 40 °C

Procedure:
A mixture of N-[(S)-6-((R)-1-aminoethyl)-1,2,3,4-tetrahydronaphthalen-2-yl]-4-[(S)-1-(tetrahydrofuran-2-yl)methoxy]benzamide (50 mg), 1,6-dibromohexane (31 mg), ethyldiisopropylamine (0.10 ml) and acetonitrile (1 ml) was heated to 40° C. for 8 hours. The cooled reaction mixture was concentrated and the residue was purified by preparative HPLC. The product was thus obtained with the molecular weight of 476.66 (C30H40N2O3); MS (ESI): 477 (M+H+).
Reaction SMILES: [C:1](OC1C(F)=C(F)C(F)=C(F)C=1F)(=[O:4])[CH:2]=[CH2:3].[CH3:17][O:18][C:19]1[CH:24]=[C:23]([N:25]2[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]2)[C:22]([NH2:32])=[CH:21][C:20]=1[NH:33][C:34]1[N:39]=[C:38]([C:40]2[CH:41]=[N:42][N:43]3[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=23)[CH:37]=[CH:36][N:35]=1>CN(C=O)C.C(Cl)Cl>[CH3:17][O:18][C:19]1[C:20]([NH:33][C:34]2[N:39]=[C:38]([C:40]3[CH:41]=[N:42][N:43]4[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=34)[CH:37]=[CH:36][N:35]=2)=[CH:21][C:22]([NH:32][C:1](=[O:4])[CH:2]=[CH2:3])=[C:23]([N:25]2[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]2)[CH:24]=1
Reactant: COc1cc(N2CCN(C)CC2)c(N)cc1Nc1nccc(-c2cnn3ccccc23)n1
Reactant: C=CC(=O)Oc1c(F)c(F)c(F)c(F)c1F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C=CC(=O)Nc1cc(Nc2nccc(-c3cnn4ccccc34)n2)c(OC)cc1N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 29.7 %

Procedure:
(2,3,4,5,6-Pentafluorophenyl) prop-2-enoate (0.030 mL, 0.19 mmol) was added dropwise to a solution of 4-methoxy-6-(4-methylpiperazin-1-yl)-N′(4-pyrazolo[1,5-a]-pyridin-3-ylpyrimidin-2-yl)benzene-1,3-diamine (Intermediate 69, 67 mg, 0.16 mmol) in DMF (0.6 mL) at r.t. under N2. The resulting solution was stirred at r.t. for 1.5 h and then diluted with CH2Cl2 (9 mL). This solution was added to 1.5 g flash silica which was wet with CH2Cl2 in a dry-loaded cartridge, and the crude product was eluted from the silica using CH2Cl2. Further purification by FCC, eluting with 2-7% of 2N methanolic ammonia in CH2Cl2 provided material which was further purified by FCC, eluting with 5-20% CH3OH in CH2Cl2. Appropriate fractions were concentrated in vacuo and trituration provided a crystalline solid that was washed with THF (0.1 mL) to give the title compound (23 mg, 28%) as a beige crystalline solid; 1H NMR: 2.33-2.43 (3H, m), 2.62-2.81 (4H, m), 2.94 (4H, s), 3.85 (3H, s), 5.72 (1H, d), 6.18 (1H, m), 6.55-6.69 (1H, m), 6.89 (1H, s), 7.05 (1H, m), 7.26 (1H, d), 7.35-7.43 (1H, m), 8.15 (1H, s), 8.34 (1H, d), 8.44 (1H, d), 8.49 (1H, s), 8.79 (1H, d), 8.80 (1H, s), 9.03 (1H, s); m/z: ES+ MH+ 485.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.[C:13](Cl)(=[O:22])[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O.Cl>N1C=CC=CC=1>[CH3:1][N:2]([C:13](=[O:22])[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: CNc1ccc(C(=O)OC)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)c1ccc(N(C)C(=O)CCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 4-methylaminobenzoate (1.0 g, 6.05 mmol) in anhydrous pyridine (20 mL) was added dropwise hydrocinnamoyl chloride (1080 μL) at rt. After 16 hrs water (5 mL) was added and the resulting mixture was stirred for 1 hr at rt. The resulting mixture was poured into water (300 mL) and HCl (5 N, 50 mL) was added. The compound was extracted with AcOEt (2×300 mL) and washed with a saturated aqueous solution of NaHCO3 (150 mL). The combined organic layers were dried over MgSO4 and evaporated under vacuo to give the title compound (1.80 g) was obtained as a beige solid (95%) in 95.3% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][OH:9])=[C:6]([C:10]2[CH:11]=[CH:12][C:13]([NH:17][CH2:18][CH3:19])=[C:14]([OH:16])[CH:15]=2)[CH:5]=[C:4]([C:20]2[C:25]([O:26]CC3C=CC(OC)=CC=3)=[CH:24][CH:23]=[CH:22][C:21]=2[O:36][CH2:37][CH:38]2[CH2:40][CH2:39]2)[N:3]=1.Cl>O1CCOCC1.C(OCC)C>[NH2:1][C:2]1[N:3]=[C:4]([C:20]2[C:21]([O:36][CH2:37][CH:38]3[CH2:40][CH2:39]3)=[CH:22][CH:23]=[CH:24][C:25]=2[OH:26])[CH:5]=[C:6]([C:10]2[CH:11]=[CH:12][C:13]([NH:17][CH2:18][CH3:19])=[C:14]([OH:16])[CH:15]=2)[C:7]=1[CH2:8][OH:9]
Reactant: CCNc1ccc(-c2cc(-c3c(OCc4ccc(OC)cc4)cccc3OCC3CC3)nc(N)c2CO)cc1O
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CCNc1ccc(-c2cc(-c3c(O)cccc3OCC3CC3)nc(N)c2CO)cc1O
Reaction time: 8 h

Procedure:
To a solution of 5-[2-amino-6-{2-(cyclopropylmethoxy)-6-[(4-methoxybenzyl)oxy]phenyl}-3-(hydroxymethyl)-4-pyridinyl]-2-(ethylamino)phenol (0.013 g, 0.023 mmol) in 1,4-dioxane (0.5 mL) was added a solution of HCl in 1,4-dioxane (4N, 1.0 mL). After being stirred overnight, the mixture was diluted with diethyl ether. The resulting precipitate was collected by filtration under argon atmosphere, washed with Et2O, and dried under reduced pressure to give 2-[6-amino-4-[4-(ethylamino)-3-hydroxyphenyl]-5-(hydroxymethyl)-2-pyridinyl]-3-(cycloproylmethoxy)phenol. (0.008 g, 76%); LC-MS (m/z=422 M+1)
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][S:7]([C:10]1[CH:11]=[N:12][C:13]([NH:16][C:17]([NH2:19])=[S:18])=[CH:14][CH:15]=1)(=[O:9])=[O:8].Br[CH2:21][C:22](=O)[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1>CN(C=O)C.CC(O)=O>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([CH2:23][C:22]2[N:19]=[C:17]([NH:16][C:13]3[N:12]=[CH:11][C:10]([S:7]([NH:6][C:2]4[S:1][CH:5]=[CH:4][N:3]=4)(=[O:8])=[O:9])=[CH:15][CH:14]=3)[S:18][CH:21]=2)=[CH:25][CH:26]=1
Reactant: NC(=S)Nc1ccc(S(=O)(=O)Nc2nccs2)cn1
Reactant: O=C(CBr)Cc1ccc(Cl)cc1
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: O=S(=O)(Nc1nccs1)c1ccc(Nc2nc(Cc3ccc(Cl)cc3)cs2)nc1
Temperature: 95 °C

Procedure:
The mixture of the 6-Thioureido-pyridine-3-sulfonic acid thiazol-2-ylamide (27 mg, 0.000086 mol) and 1-Bromo-3-(4-chloro-phenyl)-propan-2-one (25 mg, 0.00010 mol) in DMF/AcOH (1:1) was heated at 95° C. for 20 min. The reaction solution was directly purified on Gilson (semi-prep, reverse phase, Phenomenex 100×21.2 mm 10 micron C18 column, 20 mL/min, Gradient 85% A to 100% B over 25 min. Solvent A: 7800 water/200 acetonitrile/8 TFA. Solvent B: 7200 acetonitrile/800 water/8 TFA). Fractions were checked by LC/MS and found no pure desired product was isolated. Fractions with the desired product were combined and then dried on a lyophilizer to give the product (1126-8-P1) as a yellow powder. The product (a mixture) was purified again by chromatography (silica gel, 5% Ethyl acetate in hexanes to 100% Ethyl acetate) to give a cleaner product (1126-8-P2), which was purified by Prep TLC (25% Ethyl acetate in hexanes, then 100% Ethyl acetate) to give the final pure product (1126-8-P-3) as a yellow solid.
Reaction SMILES: [C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:11][CH2:12][CH2:13][NH:14][CH3:15])[C:8]([NH2:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:22][C:23]1[CH:31]=[CH:30][C:26]([CH2:27][CH2:28]Br)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:11][CH2:12][CH2:13][N:14]([CH2:28][CH2:27][C:26]2[CH:30]=[CH:31][C:23]([Cl:22])=[CH:24][CH:25]=2)[CH3:15])[C:8]([NH2:10])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CNCCCC(C(N)=O)(c1ccccc1)c1ccccc1
Reactant: Clc1ccc(CCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(CCCC(C(N)=O)(c1ccccc1)c1ccccc1)CCc1ccc(Cl)cc1

Procedure:
A mixture containing 2,2-diphenyl-5methylaminopentanamide (0.3 g--see Preparation 3), 4-chlorophenethyl bromide (0.234 g--see Preparation 7), anhydrous potassium carbonate (0.4 g) and acetonitrile (10 ml) was heated under reflux for 5 hours. The mixture was concentrated in vacuo and the residue partitioned between dichloromethane (30 ml) and 10% aqueous potassium carbonate (30 ml). The layers were separated and the aqueous layer extracted with dichloromethane (3×20 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give a gum which was purified by column chromatography on silica eluting with dichloromethane containing methanol (5% up to 10%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a gum, yield 0.306 g.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[CH:6]=[CH:7][C:8]([NH:11][C:12]3[C:13](=[O:20])[N:14]([CH3:19])[CH:15]=[C:16]([Br:18])[CH:17]=3)=[N:9][CH:10]=2)[CH2:2]1.[CH3:21][CH:22]=O.[OH-].[Na+]>CO.C(O)(=O)C>[Br:18][C:16]1[CH:17]=[C:12]([NH:11][C:8]2[CH:7]=[CH:6][C:5]([CH:3]3[CH2:4][N:1]([CH2:21][CH3:22])[CH2:2]3)=[CH:10][N:9]=2)[C:13](=[O:20])[N:14]([CH3:19])[CH:15]=1
Reactant: Cn1cc(Br)cc(Nc2ccc(C3CNC3)cn2)c1=O
Reactant: CC=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: CCN1CC(c2ccc(Nc3cc(Br)cn(C)c3=O)nc2)C1
Yield: 43 %

Procedure:
To a solution of 3-(5-(azetidin-3-yl)pyridin-2-ylamino)-5-bromo-1-methylpyridin-2(1H)-one 155n (crude, 4.6 mmol) in methanol (50 mL) and acetic acid (5 mL) at 0° C., was added CH3CHO (40% wt in H2O) (10 g, 92 mmol) followed by the addition of NaBH(CH3O)3 (20 g, 92 mmol) in small portions over a period of 1 h. After the reaction was finished, the mixture was adjusted to pH>7 with 2N NaOH. Then the mixture was extracted with DCM (80 mL×3), dried over Na2SO4 and concentrated to get a yellow solid, which was purified on flash column eluting with 50:1 DCM/MeOH containing 0.5% Et3N to afford 250a as a yellow solid (43%, two steps). LCMS: (M+H)+ 364. 1H NMR (500 MHz, DMSO) δ 8.72 (s, 1H), 8.66 (d, J=3, 1H), 8.21 (d, J=3, 1H), 7.68 (dd, J=9, 1H), 7.52 (d, J=2.5, 1H), 7.32 (d, J=9, 1H), 3.54 (m, 6H), 2.99 (m, 2H), 2.42 (m, 2H), 0.89 (t, J=7, 3H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:22]([C@@H:23]([CH3:27])[C:24]([OH:26])=O)[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[N:15]=2)=[CH:10][CH:9]=1.[CH3:28][NH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(N(CC)CC)C>CN(C)C=O>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[N:22]([C@@H:23]([CH3:27])[C:24]([N:29]([CH3:28])[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:26])[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[N:15]=2)=[CH:12][CH:13]=1
Reactant: C[C@@H](C(=O)O)n1c(-c2ccc(Cl)cc2)nc2cccnc21
Reactant: CNc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@@H](C(=O)N(C)c1ccccc1)n1c(-c2ccc(Cl)cc2)nc2cccnc21
Temperature: 50 °C
Yield: 64.7 %

Procedure:
Under a nitrogen atmosphere, oxalyl chloride (2.18 g, 0.0172 mole) was added slowly, dropwise, to a stirred and chilled (10° C.) suspension of (S)-2-(4-chlorophenyl)-α-methyl-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.0 g, 0.0166 mole) in dry dimethylformamide (75 ml). The mixture was stirred at room temperature for 3 hours, heated at 50° C. for one hour and cooled to room temperature. An additional 0.0057 mole of oxalyl chloride was added and the mixture was stirred at room temperature for 30 minutes. N-Methylaniline (1.92 g, 0.0179 mole) was added and the reaction mixture was stirred at room temperature under nitrogen overnight. The mixture was poured into 400 ml of ice water and triethylamine (6 ml) was added. The precipitated solid was collected by filtration, rinsed with water, redissolved in hot isopropyl alcohol, treated with charcoal, filtered hot and allowed to cool. Addition of water caused a solid to form. The solid was collected by filtration, rinsed with water and dried under high vacuum overnight to give 4.2 g (65%) of title compound, mp 174°-177° C.
Reaction SMILES: S(Cl)(Cl)=O.[NH2:5][CH:6]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:7][C:8]([OH:10])=[O:9].[CH3:17]O>>[NH2:5][CH:6]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:7][C:8]([O:10][CH3:17])=[O:9]
Reactant: NC(CC(=O)O)c1ccccc1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)CC(N)c1ccccc1
Reaction time: 12 h

Procedure:
Thionyl chloride (19.1 g, 162 mmol) was added dropwise to a solution, cooled to 0° C., of 3-amino-3-phenylpropionic acid (8.9 g, 54 mmol) in methanol (150 ml). The reaction mixture was then stirred for 12 h under reflux (TLC control). The solvent was removed completely and the residue was dried in vacuo. The crude product was used in the next stage without being purified further.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=CC=2F)=[CH:10][C:9]=1[NH:21][C:22](=[O:39])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([N:32]2[CH:36]=[C:35]([CH3:37])[N:34]=[C:33]2[CH3:38])[CH:27]=1)=O)(C)(C)C.[C:41](O)([C:43]([F:46])(F)F)=O>C(Cl)Cl>[CH3:38][C:33]1[N:32]([C:28]2[CH:27]=[C:26]([C:24]3[CH2:23][C:22](=[O:39])[NH:21][C:9]4[CH:10]=[C:11]([C:14]5[CH:19]=[CH:18][CH:17]=[CH:41][C:43]=5[F:46])[CH:12]=[CH:13][C:8]=4[N:7]=3)[CH:31]=[CH:30][CH:29]=2)[CH:36]=[C:35]([CH3:37])[N:34]=1
Reactant: Cc1cn(-c2cccc(C(=O)CC(=O)Nc3cc(-c4ccccc4F)ccc3NC(=O)OC(C)(C)C)c2)c(C)n1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cn(-c2cccc(C3=Nc4ccc(-c5ccccc5F)cc4NC(=O)C3)c2)c(C)n1

Procedure:
Prepared from (3-{3-[3-(2,4-dimethyl-imidazol-1-yl)-phenyl]-3-oxo-propionylamino}-2′-fluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example K70) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a yellow solid (92 mg).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:10]3[O:11][C@@H:12]([CH2:15][OH:16])[CH2:13][O:14][C:9]=3[CH:8]=[CH:7][C:5]=2[N:6]=1.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:27][C:17]1[CH:22]=[CH:21][C:20]([S:23]([O:16][CH2:15][CH:12]2[CH2:13][O:14][C:9]3[CH:8]=[CH:7][C:5]4[N:6]=[C:2]([CH3:1])[O:3][C:4]=4[C:10]=3[O:11]2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: Cc1nc2ccc3c(c2o1)O[C@@H](CO)CO3
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2COc3ccc4nc(C)oc4c3O2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of [(8S)-2-methyl-7,8-dihydro[1,4]dioxino[2,3-g][1,3]benzoxazol-8-yl]methanol (1.80 g, 8.14 mmole) in methylene chloride (100 mL) was added p-toluenesulfonyl chloride (3.90 g, 20.4 mmole). The mixture was cooled in an ice bath and a solution of diisopropylethylamine (3.55 mL, 20.4 mmole) in methylene chloride (20 mL) was then added dropwise, followed by 4-dimethylaminopyridine (0.65 g, 5.30 mmole). The solution was allowed to warm to room temperature and was stirred under nitrogen overnight. The reaction was diluted to 500 mL in volume with methylene chloride, then washed with aqueous 2 N HCl (200 mL), with saturated aqueous sodium bicarbonate (200 mL), and with brine (150 mL), dried over magnesium sulfate, filtered and evaporated in vacuum to a yellow oil. The crude oil was column chromatographed on silica gel using methylene chloride to remove impurities and 3% methanol/methylene chloride to elute the (R)-enantiomer of the title compound, which becomes a white solid under vacuum (2.56 g, 84%), m.p. 123° C. MS (ESI) m/z 376 (M+H)+.
Reaction SMILES: [C:1]([Si:5]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].C([Li])(CC)C.CN(C)CCN(C)CCN(C)C.CN([CH:39]=[O:40])C>C1COCC1>[Si:5]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[C:13]([F:18])=[C:14]([CH:15]=[CH:16][CH:17]=1)[CH:39]=[O:40])([C:1]([CH3:4])([CH3:2])[CH3:3])([CH3:7])[CH3:6]
Reactant: CN(C)C=O
Reactant: CC(C)(C)[Si](C)(C)OCCCc1ccccc1F
Agent: CN(C)CCN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCCc1cccc(C=O)c1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-Butyl(3-(2-fluorophenyl)propoxy)dimethylsilane [Aromatic Intermediate 24, step b] (4.4 g) was added dropwise over 5 min to a solution of sec-butyllithium (1.4M in cyclohexane, 11.7 mL) and 1,1,4,7,7-pentamethyldiethylenetriamine (3.4 mL) in THF (25 mL) at −78° C. The resulting mixture was stirred for 2 h, then DMF (6.4 mL) was cautiously added and the resulting mixture allowed to warm to RT and stirred overnight. The reaction was quenched with water (100 mL) and then ethyl acetate (250 mL) was added. The phases were separated and the organic phase washed with water (2×100 mL), aqueous HCl (2M, 2×50 mL), and brine (100 mL), then dried over magnesium sulphate, filtered and evaporated. Purification was by silica gel chromatography eluting with isohexane to 10% ether in isohexane gradient. The fractions containing product were combined and evaporated to give the titled compound as a clear oil. Yield 1.0 g.
Reaction SMILES: Cl[C:2]1[C:3]([C:10]([OH:12])=[O:11])=[N:4][N:5]([CH3:9])[C:6](=[O:8])[CH:7]=1.[F:13][C:14]1[CH:20]=[C:19]([I:21])[CH:18]=[CH:17][C:15]=1[NH2:16].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>O1CCCC1>[F:13][C:14]1[CH:20]=[C:19]([I:21])[CH:18]=[CH:17][C:15]=1[NH:16][C:2]1[C:3]([C:10]([OH:12])=[O:11])=[N:4][N:5]([CH3:9])[C:6](=[O:8])[CH:7]=1
Reactant: Cn1nc(C(=O)O)c(Cl)cc1=O
Reactant: Nc1ccc(I)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cn1nc(C(=O)O)c(Nc2ccc(I)cc2F)cc1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 130.1 %

Procedure:
To a solution of 4-chloro-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylic acid (350 mg, 1.855 mmol) and 2-fluoro-4-iodoaniline (1.06 g, 4.453 mmol) in tetrahydrofuran (13.3 mL) was sparged with nitrogen for 5 minutes followed by the slow addition of lithium bis(trimethylsilyl)amide, 1.0 M in THF (7.4 mL). The reaction mixture stirred for an additional 4 hours at room temperature. The mixture was quenched with 1 N HCl and concentrated in vacuo. The residue was partitioned between ethyl acetate and 1 N aqueous HCl. The aqueous layer was extracted (3×) with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated to afford 4-(2-fluoro-4-iodophenylamino)-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylic acid (939 mg, 100% yield). 1H NMR (CDCl3): 7.27 (dd, 1H), 7.21 (d, 1H), 6.54 (t, 1H), 4.84 (broad s, 2H), 2.09 (s, 1H), 1.26 (t, 3H); MS (EI) for C12H9N3O3FI: 389 (MH+).