Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[S:4][C:3]1=S.C1(C)C=CC(S(OC)(=O)=O)=CC=1.C1(OC)C=CC=CC=1.[CH2:35]([N:42]1[C:46](=[O:47])[CH2:45][S:44][C:43]1=[N:48][C:49]1[CH:50]=[C:51]([CH:54]=[CH:55][C:56]=1[NH:57][CH2:58][CH3:59])[C:52]#[N:53])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>CC#N>[CH2:35]([N:42]1[C:46](=[O:47])[C:45](=[C:3]2[N:2]([CH3:1])[C:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[C:5]([CH3:13])[S:4]2)[S:44][C:43]1=[N:48][C:49]1[CH:50]=[C:51]([CH:54]=[CH:55][C:56]=1[NH:57][CH2:58][CH3:59])[C:52]#[N:53])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: Cc1sc(=S)n(C)c1-c1ccccc1
Reactant: CCNc1ccc(C#N)cc1N=C1SCC(=O)N1Cc1ccccc1
Agent: COS(=O)(=O)c1ccc(C)cc1
Solvent: COc1ccccc1
Solvent: CC#N
Product: CCNc1ccc(C#N)cc1N=C1SC(=C2SC(C)=C(c3ccccc3)N2C)C(=O)N1Cc1ccccc1
Temperature: 120 °C
Reaction time: 3 h
Yield: 64.2 %

Procedure:
To an 8 mL vial was added 3,5-dimethyl-4-phenyl-3H-thiazole-2-thione (100 mg, 0.45 mmol), methyl p-toluenesulfonate (126 mg, 0.68 mmol) and anhydrous anisole (0.5 mL). The reaction was heated to 120° C. and stirred for 3 h. The cooled reaction mixture was diluted with anhydrous MeCN (3 mL) and then treated with 3-(3-benzyl-4-oxothiazolidin-2-ylideneamino)-4-(ethylamino)benzonitrile (50 mg, 0.14 mmol) and TEA (70 μL, 0.50 mmol). The reaction mixture was warmed to 80° C. and the resulting solution was allowed to stir for 16 h. The product mixture was concentrated under reduced pressure and chromatographed (silica gel, 1:1 EtOAc/Hex) to yield the title product (48.3 mg, 64%) as a yellow solid. 1H-NMR (CDCl3): δ 7.40 (5H, m) 7.33 (2H, m), 7.25 (3H, m), 7.23 (2H, m), 6.46 (1H, d), 5.15 (2H, s), 4.28 (1H, m), 3.46 (3H, s), 2.99 (2H, m), 2.28 (3H, s), 1.01 (3H, t); MS(ESI): 538 (MH+).
Reaction SMILES: [NH:1]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C@H:2]([C:10]([NH:12][C@H:13]([C:20](O)=[O:21])[CH2:14][C:15]1[N:19]=[CH:18][NH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:33][C@H:34]([C:39]([NH:41][C@H:42]([C:46]([NH:48][C@H:49]([C:54]([OH:56])=[O:55])[C@H:50]([CH2:52][CH3:53])[CH3:51])=[O:47])[CH:43]([CH3:45])[CH3:44])=[O:40])[CH2:35][CH:36]([CH3:38])[CH3:37].[C:57]([CH2:60][C:61]1[N:62]=[C:63]([NH-:66])[S:64][CH:65]=1)(=[O:59])[NH2:58].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>>[NH:1]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C@H:2]([C:10]([NH:12][C@H:13]([C:20]([NH:33][C@H:34]([C:39]([NH:41][C@H:42]([C:46]([NH:48][C@H:49]([C:54]([OH:56])=[O:55])[C@H:50]([CH2:52][CH3:53])[CH3:51])=[O:47])[CH:43]([CH3:44])[CH3:45])=[O:40])[CH2:35][CH:36]([CH3:37])[CH3:38])=[O:21])[CH2:14][C:15]1[N:19]=[CH:18][NH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:57]([CH2:60][C:61]1[N:62]=[C:63]([NH-:66])[S:64][CH:65]=1)(=[O:59])[NH2:58]
Reactant: CC[C@H](C)[C@H](NC(=O)[C@@H](NC(=O)[C@@H](N)CC(C)C)C(C)C)C(=O)O
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Agent: [NH-]c1nc(CC(N)=O)cs1
Product: CC[C@H](C)[C@H](NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(C)C)C(=O)O

Procedure:
In a manner analogous to that described in Example 1, using as starting materials 81 mg of Z-Phe-His-OH, 69 mg of H-Leu-Val-Ile-4-(carbamoylmethyl)-2-thiazolyl amide, 28 mg of HOBt and 39 mg of DCCI, the title compound is obtained after flash chromatography (65 g of silica gel 60, 40-63 μm, eluant system B7). Rf (B7)=0.21.
Reaction SMILES: [F:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[CH:5]=[C:4]([CH2:12][C:13]#[N:14])[CH:3]=1.[H-].[Na+].[C:17](OCC)(=[O:19])[CH3:18].O>C1COCC1>[F:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[CH:5]=[C:4]([CH:12]([C:17](=[O:19])[CH3:18])[C:13]#[N:14])[CH:3]=1
Reactant: CCOC(C)=O
Reactant: N#CCc1cc(F)c2c(c1)OCCO2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)C(C#N)c1cc(F)c2c(c1)OCCO2
Temperature: 60 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
To a solution of (8-fluoro-2,3-dihydro-1,4-benzodioxin-6-yl)acetonitrile (0.40 g, 2.10 mmol) in THF (10 mL) was added sodium hydride (60% dispersion in mineral oil, 0.25 g, 6.3 mmol) and ethyl acetate (2.05 ml, 21.0 mmol) and the mixture was stirred at 60° C. for 2 h. After cooling to 0° C., water was added (25 mL) and the aqueous layer was washed with dichloromethane (3×15 mL), acidified with 1N HCl to pH 3 and extracted with ethyl acetate (3×25 mL). The combined organic extracts were washed with brine (30 mL) then dried with sodium sulfate, filtered and concentrated to give 2-(8-fluoro-2,3-dihydro-1,4-benzodioxin-6-yl)-3-oxobutanenitrile as an orange solid (0.37 g; 75% yield). 1H NMR (400 MHz, d6-DMSO) δ 7.05 (dd, 1H), 6.93 (br. s, 1H), 4.30 (m, 5H), 2.30 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17]Cl)[C:12]=2[CH2:19][CH3:20])[CH:3]=1.[NH3:21].[C:22]([OH:29])(=[O:28])/[CH:23]=[CH:24]/[C:25]([OH:27])=[O:26]>CO>[C:22]([OH:29])(=[O:28])/[CH:23]=[CH:24]/[C:25]([OH:27])=[O:26].[NH2:21][CH2:17][C:13]1[C:12]([CH2:19][CH3:20])=[C:11]([CH:16]=[CH:15][CH:14]=1)[O:10][C:4]1[CH:3]=[C:2]([Cl:1])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7].[NH2:21][CH2:17][C:13]1[C:12]([CH2:19][CH3:20])=[C:11]([CH:16]=[CH:15][CH:14]=1)[O:10][C:4]1[CH:3]=[C:2]([Cl:1])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: CCc1c(CCl)cccc1Oc1cc(Cl)ccc1C#N
Reactant: N
Agent: O=C(O)/C=C/C(=O)O
Solvent: CO
Product: CCc1c(CN)cccc1Oc1cc(Cl)ccc1C#N
Temperature: 25 °C
Reaction time: 96 h
Yield: 95.2 %

Procedure:
To a solution of 4-chloro-2-(3-chloromethyl-2-ethyl-phenoxy)-benzonitrile (0.16 g, 0.53 mmol) in methanol (10 mL) was added ammonia (7N in methanol, 15 mL, 105 mmol), and the reaction mixture stirred for 4 days at ambient temperature. The solvent was removed in vacuo. The residue was treated with 10% sodium carbonate solution and extracted with ethyl acetate. The ethyl acetate layer was separated and a solution of fumaric acid (60 mg, 0.52 mmol) in methanol (3 mL) was added. After thc solvent was removed in vacuo, the residue was triturated with diethyl ether overnight, collected by filtration, and dried to give 2-(3-aminomethyl-2-ethyl-phenoxy)-4-chloro-benzonitrile hemifumarate (174 mg, 83%) as a white solid.
Reaction SMILES: [O:1]=[C:2]1[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][N:3]1[CH2:19][C:20](O)=[O:21].FC1C=CC(C2(C3C=CC(F)=CC=3)CCN(CC(O)=O)C2=O)=CC=1.[Cl:47][C:48]1[CH:58]=[CH:57][C:51](/[C:52](=[N:55]/[H])/[NH:53]O)=[CH:50][CH:49]=1.ON/C(=N\[H])/C1C=CC(C(F)(F)F)=CC=1>>[Cl:47][C:48]1[CH:58]=[CH:57][C:51]([C:52]2[N:55]=[C:20]([CH2:19][N:3]3[CH2:4][CH2:5][C:6]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:2]3=[O:1])[O:21][N:53]=2)=[CH:50][CH:49]=1
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Reactant: [H]/N=C(\NO)c1ccc(Cl)cc1
Agent: O=C(O)CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Agent: [H]/N=C(\NO)c1ccc(C(F)(F)F)cc1
Product: O=C1N(Cc2nc(-c3ccc(Cl)cc3)no2)CCC1(c1ccccc1)c1ccccc1

Procedure:
The title compound was prepared using the procedure described in Example 190 substituting 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid from Example 1C for 2-(3,3-bis(4-fluorophenyl)-2-oxopyrrolidin-1-yl)acetic acid and (Z)-4-chloro-N-hydroxybenzimidamide for (Z)—N-hydroxy-4-(trifluoromethyl)benzimidamide. 1H NMR (300 MHz, CDCl3) δ ppm 7.99-7.91 (m, 2H), 7.49-7.14 (m, 12H), 4.88 (s, 2H), 3.57 (t, J=6.5, 2H), 2.89 (t, J=6.5, 2H); MS (DCI) m/z 430.1 (M+H)+.
Reaction SMILES: Cl.[C:2]1([C@@H:14]2[CH2:18][CH2:17][C@H:16]([NH2:19])[CH2:15]2)[N:6]2[C:7]3[CH:13]=[CH:12][NH:11][C:8]=3[N:9]=[CH:10][C:5]2=[N:4][N:3]=1.[CH:20]1([S:23](Cl)(=[O:25])=[O:24])[CH2:22][CH2:21]1>CN(C=O)C.O>[C:2]1([C@@H:14]2[CH2:18][CH2:17][C@H:16]([NH:19][S:23]([CH:20]3[CH2:22][CH2:21]3)(=[O:25])=[O:24])[CH2:15]2)[N:6]2[C:7]3[CH:13]=[CH:12][NH:11][C:8]=3[N:9]=[CH:10][C:5]2=[N:4][N:3]=1
Reactant: N[C@H]1CC[C@@H](c2nnc3cnc4[nH]ccc4n23)C1
Reactant: O=S(=O)(Cl)C1CC1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: O=S(=O)(N[C@H]1CC[C@@H](c2nnc3cnc4[nH]ccc4n23)C1)C1CC1
Reaction time: 1.5 h
Yield: 63.8 %

Procedure:
To a mixture of (1S,3R)-3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanamine hydrochloride (0.300 g, 0.952 mmol, Example #6, Step C) in DMF (9 mL) was added TEA (0.462 mL, 3.33 mmol) and cyclopropanesulfonyl chloride (0.097 mL, 0.95 mmol). After about 1.5 h at ambient temperature, the reaction was diluted with water (10 mL) and extracted with DCM (3×15 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. To the crude material was added MeOH (˜50 mL) and a small amount of insoluble material (<0.01 g) was removed by filtration. Silica gel (2 g) was added to the filtrate and the mixture was concentrated under reduced pressure. The mixture was purified by silica gel chromatography eluting with a step-wise gradient of DCM/MeOH/NH4OH 990:9:1 to 980:18:2 to give an off-white solid that was dried in a vacuum oven at about 70° C. The solid was dissolved in hot MeOH, filtered while hot to remove particulates and then the filtrate was sonicated while cooling to provide a fine suspension which was concentrated under reduced pressure and dried in a vacuum oven at about 100° C. to give N-((1S, 3R)-3-(6H-pyrrolo[2,3-e][1, 2, 4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)cyclopropanesulfonamide (0.21 g, 64%): LC/MS (Table 2, Method a) Rt=1.51 min; MS m/z: 347 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][C:10]3[C:15]([C:16]=2[C:17]2[CH:18]=[C:19]([NH2:23])[CH:20]=[CH:21][CH:22]=2)=[CH:14][CH:13]=[CH:12][C:11]=3[C:24]([F:27])([F:26])[F:25])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[N:35]=[C:36]=[O:37]>C(N(CC)CC)C>[Cl:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[NH:35][C:36]([NH:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:16]2[C:15]3[C:10](=[C:11]([C:24]([F:27])([F:25])[F:26])[CH:12]=[CH:13][CH:14]=3)[N:9]=[CH:8][C:7]=2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:18]=1)=[O:37]
Reactant: Nc1cccc(-c2c(-c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: O=C=Nc1ccccc1Cl
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc(-c2c(-c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1)Nc1ccccc1Cl

Procedure:
The title compound was prepared from {3-[3-phenyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 2-chlorophenyl isocyanate in substantially the same manner as described in Example 61 with one change: no triethylamine was used; off-white solid: mp 192-195° C.; MS (ES) m/z 515.8.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:6]=[C:5]([O:15][CH:16]2[CH2:33][CH:32]3[CH:18]([C:19](=[O:39])[N:20]([CH3:38])[CH2:21][CH2:22][CH2:23][CH2:24][CH:25]=[CH:26][CH:27]4[C:29]([C:35]([OH:37])=O)([NH:30][C:31]3=[O:34])[CH2:28]4)[CH2:17]2)[CH:4]=1.CCN=C=NCCCN(C)C.[C:51]1([S:57]([NH2:60])(=[O:59])=[O:58])[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1.C1CCN2C(=NCCC2)CC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:6]=[C:5]([O:15][CH:16]2[CH2:33][CH:32]3[CH:18]([C:19](=[O:39])[N:20]([CH3:38])[CH2:21][CH2:22][CH2:23][CH2:24][CH:25]=[CH:26][CH:27]4[C:29]([C:35]([NH:60][S:57]([C:51]5[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=5)(=[O:59])=[O:58])=[O:37])([NH:30][C:31]3=[O:34])[CH2:28]4)[CH2:17]2)[CH:4]=1
Reactant: COc1cc(OC2CC3C(=O)NC4(C(=O)O)CC4C=CCCCCN(C)C(=O)C3C2)nc(-c2ccccc2)n1
Reactant: NS(=O)(=O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: COc1cc(OC2CC3C(=O)NC4(C(=O)NS(=O)(=O)c5ccccc5)CC4C=CCCCCN(C)C(=O)C3C2)nc(-c2ccccc2)n1
Temperature: 25 °C

Procedure:
Compound 7e (60 mg, 0.112 mmol) was dissolved in DCM (5 ml). EDAC (26 mg, 0.135 mmol) was added and the reaction mixture was stirred at RT over night. benzensulfonamide (19 mg, 0.123 mmol) and DBU (35 μl, 0.235 mmol) were added and the reaction mixture was stirred at RT for 2 h. Citric acid (5%) was added, the organic layer was separated, washed with brine, dried, filtered and evaporated. The residue was purified by preparative HPLC which gave the pure title compound. (36 mg, 48%), MS (M+H)+674.
Reaction SMILES: C(Cl)(=O)C(Cl)=[O:3].CS(C)=O.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:21](O)[CH2:22][CH3:23])[CH:16]=[CH:17][C:18]=1[O:19][CH3:20].C(N(CC)CC)C>ClCCl>[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[CH2:21][CH2:22][CH:23]=[O:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCC(O)c1ccc(OC)c(OC)c1
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CCC=O)cc1OC
Temperature: -45 °C
Yield: 70.7 %

Procedure:
To a solution of oxalyl chloride(0.67 ml) in dichloromethane (80 ml) was added dropwise a solution of DMSO (1.18 ml) in dichloromethane(5 ml) at −78° C. To the mixture was added a solution of 1-(3,4-dimethoxyphenyl)propanol (1.50 g) in dichloromethane(25 ml) after 15 minutes. The mixture was stirred for an hour at −78° C. and for another hour at −45° C., then triethylamine(3.52 ml) was added. After stirring 20 minutes at 0° C., the mixture was quenched by a saturated aqueous NH4Cl solution, and extracted with dichloromethane. The organic layer was dried over MgSO4 and evaporated in vacuo. The residue was purified by a silica gel column chromatography eluting with a mixture of ethyl acetate and n-hexane (1:7 to 1:1) to give 3,4-dimethoxy-hydrocinnamaldehyde (1.05 g, 70.7%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:4]=1[CH:5]=[CH:6][C:7]([OH:9])=[O:8].[H][H].[CH3:18]O>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:4]=1[CH2:5][CH2:6][C:7]([O:9][CH3:18])=[O:8]
Reactant: CO
Reactant: COc1ccc(C=CC(=O)O)c(OC)c1
Reactant: [H][H]
Solvent: CCOC(C)=O
Product: COC(=O)CCc1ccc(OC)cc1OC
Reaction time: 48 h

Procedure:
20.8 g of 2,4-dimethoxycinnamic acid are dissolved in a hot mixture of 500 ml of methanol and 100 ml of ethyl acetate and, after addition of 1 g of catalyst (10% Pd/C), hydrogenated under atmospheric pressure. The uptake of hydrogen ought to be complete after 3 hours. If the hydrogenation is incomplete, more fresh catalyst is added. After the reaction is complete, the catalyst is removed, the solution is concentrated to about 200 ml, 20 ml of an approx. 2.4 M methanolic hydrochloric acid solution are added, and the mixture is left to stand at room temperature for 2 days. The esterification is then complete. The methanol is removed in vacuo, the residue is taken up in 200 ml of ethyl acetate, and the organic phase is washed with NaHCO3 solution and saturated NaCl solution (50 ml each 3 times), dried over Na2SO4 and concentrated.
Reaction SMILES: [F:1][C:2]1[C:3]2[N:4]([CH:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][C:7]=1[C:8]([OH:11])([CH3:10])[CH3:9].Br[C:16]1[CH:17]=[CH:18][C:19]([F:30])=[C:20]([CH:29]=1)[O:21][CH2:22][C:23]1[N:24]=[N:25][N:26]([CH3:28])[CH:27]=1>>[F:1][C:2]1[C:3]2[N:4]([C:12]([C:16]3[CH:17]=[CH:18][C:19]([F:30])=[C:20]([O:21][CH2:22][C:23]4[N:24]=[N:25][N:26]([CH3:28])[CH:27]=4)[CH:29]=3)=[CH:13][N:14]=2)[CH:5]=[CH:6][C:7]=1[C:8]([OH:11])([CH3:10])[CH3:9]
Reactant: Cn1cc(COc2cc(Br)ccc2F)nn1
Reactant: CC(C)(O)c1ccn2ccnc2c1F
Product: Cn1cc(COc2cc(-c3cnc4c(F)c(C(C)(C)O)ccn34)ccc2F)nn1

Procedure:
2-(8-Fluoroimidazo[1,2-α]pyridin-7-yl)propan-2-ol was coupled to 4-(5-bromo-2-fluorophenoxymethyl)-1-methyl-1H-[1,2,3]triazole as described in Example 6 to give 2-{8-fluoro-3-[4-fluoro-3-(1-methyl-1H-[1,2,3]triazol-4-ylmethoxy)phenyl]imidazo[1,2-α]pyridin-7-yl}propan-2-ol as an off-white solid: δH (400 MHz, d6-DMSO) 1.58 (6H, s), 4.07 (3H, s), 5.35 (2H, s), 5.55 (1H, s), 7.16-7.23 (2H, m), 7.37 (1H, dd, J 11 and 9), 7.65 (1H, dd, J 8 and 2), 7.76 (1H, s), 8.21 (1H, s), 8.43 (1H, d, J 7); m/z (ES+) 400 [MH+].
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2OC2C=CC(OCC3C=CC=CC=3)=CC=2)[N:5]=[CH:4][N:3]=1.[H][H].CN(C)[C:31](=[O:33])[CH3:32]>[Pd]>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[C:6]2[CH:7]=[CH:8][C:31]([OH:33])=[CH:32][CH:11]=2)[N:5]=[CH:4][N:3]=1
Reactant: CC(=O)N(C)C
Reactant: Nc1ncnc2cccc(Oc3ccc(OCc4ccccc4)cc3)c12
Reactant: [H][H]
Agent: [Pd]
Product: Nc1ncnc2cccc(-c3ccc(O)cc3)c12
Yield: 27.3 %

Procedure:
4-Amino-5-(4-benzyloxyphenoxy)quinazoline (1.5 g, 4.4 mmol) was heated at 50-60° C. under 5 atmospheres of hydrogen gas in the presence of 0.5 g of 10% palladium on carbon in 80 mL of N,N-dimethylacetamide. After 4 hours the reaction mixture was filtered through a fritted glass funnel containing silica gel, concentrated, dissolved in 80 mL of ethanol/water 4/1 (v/v) and allowed to crystallize at 4° C. The precipitate was collected by vacuum filtration, washed with ethanol and dried at 150° C. under vacuum to give 0.3 g (27.3% yield) of 4-amino-5-(4-hydroxyphenyl)quinazoline, m.p. 300-302° C. (dec).
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[CH:5][C:6]=1[C:7]([CH2:9][C:10]#[N:11])=[O:8].F[C:13]1C=CC(NN)=CC=1.[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[NH:29][NH2:30]>>[NH2:11][C:10]1[N:29]([C:23]2[CH:24]=[CH:25][C:26]([F:28])=[CH:27][C:22]=2[F:21])[N:30]=[CH:13][C:9]=1[C:7]([C:6]1[CH:5]=[CH:4][O:3][C:2]=1[CH3:1])=[O:8]
Reactant: NNc1ccc(F)cc1F
Reactant: Cc1occc1C(=O)CC#N
Reactant: NNc1ccc(F)cc1
Product: Cc1occc1C(=O)c1cnn(-c2ccc(F)cc2F)c1N

Procedure:
Proceeding as described in Example 1, step 2, but replacing 2-(3-bromobenzoyl)acetonitrile with 2-(2-methyl-3-furanoyl)acetonitrile and substituting 4-fluorophenylhydrazine in step 3 with 2,4-difluorophenylhydrazine was obtained 5-amino-1-(2,4-difluorophenyl)-4-(2-methylfuran-3-oyl)-pyrazole (116).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([CH2:18][CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([C:15]([OH:17])=O)[CH:9]=2)=[O:4].[C:24]([CH:28]1[CH2:33][CH2:32][CH:31]([NH2:34])[CH2:30][CH2:29]1)([CH3:27])([CH3:26])[CH3:25].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([CH2:18][CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23]2)[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([C:15](=[O:17])[NH:34][CH:31]1[CH2:32][CH2:33][CH:28]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:29][CH2:30]1)[CH:9]=2)=[O:4]
Reactant: CC(C)(C)C1CCC(N)CC1
Reactant: COC(=O)c1cc2ccc(C(=O)O)cc2c(CC2CCCC2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1cc2ccc(C(=O)NC3CCC(C(C)(C)C)CC3)cc2c(CC2CCCC2)n1
Yield: 104.5 %

Procedure:
A solution of 1-cyclopentylmethyl-isoquinoline-3,7-dicarboxylic acid 3-methyl ester (38 mg, 0.121 mmol) in DMF(1.5 mL) was treated with 4-tert-butylcyclohexylamine (0.028 g, 0.181 mmol), HBTU (69 mg, 0.181 mmol), and DIEA (0.075 mL, 0.424 mmol) by the General Procedure A to give 57 mg of the desired 7-(4-tert-butyl-cyclohexylcarbamoyl)-1-cyclopentylmethyl-isoquinoline-3-carboxylic acid methyl ester as a colorless oil. This was used directly for the next step without purification.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.[NH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28].C(N(C(C)C)CC)(C)C>C(Cl)Cl.CN(C=O)C>[OH:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([NH:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:6]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCCNC(=O)c1ccc(C(F)(F)F)cc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.8 %

Procedure:
To a solution of 2-hydroxy-4-(trifluoromethyl)benzoic acid (0.5 g, 2.4 mmol) in CH2Cl2 (8 mL) was added oxalyl chloride (0.46 g, 3.6 mmol) and 2 drops of DMF. The reaction was stirred (RT, 2 h) and then concentrated under reduced pressure. The resulting residue was dissolved in CH2Cl2 (8 mL) and tert-butyl 2-aminoethylcarbamate (0.39 g, 2.4 mmol) and diisopropylethylamine (0.41 g, 3.2 mmol) were added. The reaction was stirred (RT, 16 h) and then partitioned between CH2Cl2 and brine. The aqueous layer was extracted with CH2Cl2 and the combined organic extracts were dried over MgSO4. The crude material was purified by silica gel chromatography (0-10% MeOH/CH2Cl2) to afford tert-butyl 2-(2-hydroxy-4-(trifluoromethyl)benzamido)ethylcarbamate (0.55 g). Mass calculated for C15H19F3N2O4=348.32; found: [M+Na]+=371.1. This was then dissolved in CH2Cl2 (10 mL) and TFA (4 mL). The reaction was stirred (RT, 3 h) and concentrated and dried to afford N-(2-aminoethyl)-2-hydroxy-4-(trifluoromethyl)benzamide (0.7 g) as a clear oil. Mass calculated for C10H11F3N2O2=248.20; found: [M+H]+=249.1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([C:13]#[N:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:16][OH:17].C([O-])(O)=O.[Na+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([C:13](=[NH:14])[NH:16][OH:17])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](C#N)C1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@@H](C(=N)NO)C1
Reaction time: 4 h
Yield: 77.8 %

Procedure:
(R)-3-Cyano-pyrrolidine-1-carboxylic acid tert-butyl ester (1.02 g, 5.2 mmol), hydroxylamine hydrochloride (396 mg, 5.7 mmol) and NaHCO3 (487 mg, 5.8 mmol) were added to MeOH (12 mL) and the solution was heated to reflux. After 4 h, the reaction was concentrated in vacuo. The residue was partitioned between EtOAc and brine. The layers were separated and the organic layer was dried over Na2SO4, filtered and concentrated to yield 927 mg of crude (R)-3-(N-hydroxycarbamimidoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester as a yellow foam.
Reaction SMILES: [K].[CH3:2][O:3][C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[OH:13].[CH3:14][C:15]1([O:18][CH2:17]1)[CH3:16].C1(O)C=CC=CC=1>O.CC#N>[CH3:2][O:3][C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[O:13][CH2:14][C:15]([CH3:17])([OH:18])[CH3:16]
Reactant: CC1(C)CO1
Reactant: COc1cc([N+](=O)[O-])ccc1O
Agent: [K]
Solvent: O
Solvent: CC#N
Solvent: Oc1ccccc1
Product: COc1cc([N+](=O)[O-])ccc1OCC(C)(C)O
Temperature: 170 °C
Yield: 98.6 %

Procedure:
A steel bomb, fitted with an internal thermocouple, pressure gauge and safety release valve rated at 3000 psi, with ˜55 mL capacity was charged with the potassium salt of 2-methoxy-4-nitrophenol (6 g, 29 mmol), NaH2PO4 (3.3 g, 27.7 mmol), isobutylene oxide (2.8 g, 35 mmol) and 30 mL of 15% H2O/MeCN. The sealed bomb was heated at 170° C. for three hr. Following cooling, HPLC revealed all starting phenol had been converted to product. The biphasic solution was concentrated using a rotary evaporator before being partitioned between CH2Cl2 and H2O. The aqueous phase was extracted 3× with CH2Cl2; the combined CH2Cl2 fractions were washed 3× with aq KHCO3/K2CO3 and once with H2O. After drying over Na2SO4, concentration under vacuum yielded 6.9 g of desired product as a tan solid.