Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:16][N:17]1[CH2:43][CH2:42][C:20]2[N:21]([CH2:29][CH:30](OS(C)(=O)=O)[C:31]3[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=3)[C:22]3[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][C:27]=3[C:19]=2[CH2:18]1>CN(C=O)C.O>[CH3:16][N:17]1[CH2:43][CH2:42][C:20]2[N:21]([CH2:29][CH:30]([O:8][C:1](=[O:9])[C:2]3[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=3)[C:31]3[CH:32]=[CH:33][N:34]=[CH:35][CH:36]=3)[C:22]3[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][C:27]=3[C:19]=2[CH2:18]1
Reactant: Cc1ccc2c(c1)c1c(n2CC(OS(C)(=O)=O)c2ccncc2)CCN(C)C1
Reactant: O=C(O)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2CC(OC(=O)c2ccncc2)c2ccncc2)CCN(C)C1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 6.2 %

Procedure:
To a solution of isonicotinic acid (200 mg, 1.626 mmol) in DMF (10 mL) was added potassium carbonate (560 mg, 4.065 mmol) and stirred the solution at 80° C. for 30 min. Methanesulfonic acid 2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-pyridin-4-yl-ethyl ester (455 mg, 1.138 mmol) was added portionwise into the reaction mixture, which was stirred at 80° C. 30 min. The progress of reaction was monitored by LCMS and TLC. The reaction mixture was cooled to RT, diluted with water (30 mL) and extracted with EtOAc (2×50 mL). The combined organic layer was washed with water (4×50 mL), dried over anhydrous sodium sulfate and concentrated. The residue was purified by reverse phase HPLC to yield isonicotinic acid 2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-pyridin-4-yl-ethylester (30 mg). 1H NMR (CDCl3, freebase) δ (ppm): 8.79 (d, 2H), 8.58 (d, 2H), 7.77 (d, 2H), 7.23 (d, 1H), 7.18 (s 1H), 7.12 (d, 2H), 7.0 (d, 1H), 6.24 (t, 1H), 4.54 (dd, 1H), 4.35 (dd, 1H), 3.68 (s, 2H), 2.76 (t, 2H), 2.61 (m, 1H), 2.51 (s, 3H), 2.43 (s, 3H), 2.43 (m, 1H). Separation by chiral HPLC provided enantiomers 147a and 147b.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH2:14][CH3:15])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[CH:58]1([CH2:63][C:64]2[O:68][N:67]=[C:66]([NH2:69])[CH:65]=2)[CH2:62][CH2:61][CH2:60][CH2:59]1>ClCCl.CCOC(C)=O>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([C:10](=[O:12])[NH:69][C:66]1[CH:65]=[C:64]([CH2:63][CH:58]2[CH2:59][CH2:60][CH2:61][CH2:62]2)[O:68][N:67]=1)[CH2:13][CH2:14][CH3:15])([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1cc(CC2CCCC2)on1
Reactant: CCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCC(NC(=O)OC(C)(C)C)C(=O)Nc1cc(CC2CCCC2)on1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
(S)-2-tert-Butoxycarbonylamino-pentanoic acid (21.7 mmol) was dissolved in 100 mL of dichloromethane at rt under N2. Diisopropylethylamine (43.3 mmol) was added, followed by PyBOP (32.5 mmol). The reaction was stirred for 10 minutes at rt. The isoxazole R (21.7 mmol) was separately dissolved in 25 mL of dichloromethane and then added to the reaction solution. The resultant mixture was stirred at rt for 36-48 hours. The crude material was then diluted in 200 mL EtOAc and washed with two 100 mL portions of water, followed by 100 mL of brine. The organics were then dried over Na2SO4, filtered and concentrated under reduced pressure. The crude products were purified through flash chromatography on silica gel to give [1-(5-Cyclopentylmethyl-isoxazol-3-ylcarbamoyl)-butyl]-carbamic acid tert-butyl ester (14.0 mmol).
Reaction SMILES: [OH:1][C@H:2]([C@@H:20]([NH2:28])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:3][N:4]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].C([O-])([O-])=O.[K+].[K+].[CH2:35]([O:42][C:43](Cl)=[O:44])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.OS([O-])(=O)=O.[K+]>O1CCOCC1.O>[OH:1][C@H:2]([C@@H:20]([NH:28][C:43]([O:42][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:44])[CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH2:3][N:4]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:7]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NN(Cc1ccccc1)C[C@H](O)[C@@H](N)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NN(Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1

Procedure:
Under a nitrogen atmosphere, 220 mg (0.57 mmol) of 1-[2(S)-hydroxy-3(S)-amino-4-phenyl-butyl]-1-[phenylmethyl]-2-[tert-butoxycarbonyl]-hydrazine (=H-[PheNNPhe]-Boc, Example 30b) in 15 ml of dioxane/water 1:1 and 408 mg (2.9 mmol) of K2CO3 are reacted with 120 mg (0.69 mmol) of chloroformic acid benzyl ester for 16 h at RT. KHSO4 solution is added, the mixture is extracted with 3 portions of ethyl acetate, and the organic phases are washed with water and brine, dried with Na2SO4 and concentrated by evaporation. Digestion from hexane yields the pure title compound: TLC Rf (I)=0.52; tRet (V)=17.1 min; FAB-MS (M+H)+ =520.
Reaction SMILES: [CH2:1]([O:4][C:5]([C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([N+:16]([O-])=O)[CH:15]=1)[C:10]([NH2:12])=[O:11])=[O:6])[CH:2]=[CH2:3].Cl[Sn]Cl>>[CH2:1]([O:4][C:5]([C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([NH2:16])[CH:15]=1)[C:10]([NH2:12])=[O:11])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)c1cc(C(N)=O)cc([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Product: C=CCOC(=O)c1cc(N)cc(C(N)=O)c1
Yield: 56.8 %

Procedure:
3-Allyloxycarbonyl-5-nitrobenzamide (1 g) was reduced with SnCl2 by a similar method to the reduction in example 12, giving 3-allyloxycarbonyl-5-aminobenzamide (0.5 g). Nmr (DMSO-d6): 4.78 (dt, 2H); 5.2-5.8 (broad, 2H); 5.26-5.45 (m, 2H); 5.91-6.13 (m, 1H); 7.22 (broad s, 1H); 7.27 (t, 1H); 7.33 (t, 1H); 7.59 (s, 1H).
Reaction SMILES: CCN(CCNC(C1C=CC(N)=CC=1)=O)CC.CCN(CCNC(C1C=CC(N)=C([Cl:35])C=1)=O)CC.[CH3:36][CH2:37][N:38]([CH2:41][CH2:42][NH:43][C:44]([C:46]1[CH:47]=[C:48]([Cl:55])[C:49]([NH2:54])=[CH:50][C:51]=1OC)=[O:45])[CH2:39][CH3:40].C(N)(=O)C1C=CC=NC=1.C(N(CC)CCC1N=CC=CC=1C(N)=O)C>>[ClH:35].[CH2:39]([N:38]([CH2:37][CH3:36])[CH2:41][CH2:42][NH:43][C:44](=[O:45])[C:46]1[CH:51]=[CH:50][C:49]([NH2:54])=[C:48]([Cl:55])[CH:47]=1)[CH3:40]
Reactant: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1OC
Agent: CCN(CC)CCNC(=O)c1ccc(N)c(Cl)c1
Agent: CCN(CC)CCNC(=O)c1ccc(N)cc1
Agent: CCN(CC)CCc1ncccc1C(N)=O
Product: Cl

Procedure:
Reaction of aryl carboxamides with radiation. Aqueous 100 μM solutions of procainamide (4-amino-N-(2-diethylamino-ethyl)benzamide), 3-chloro-procainamide (N-(2-diethylamino-ethyl)-4-amino-3-chlorobenzamide), metoclopramide (4-amino-5-chloro-N-(2-diethylamino-ethyl)-2-methoxybenzamide), nicotinamide and N-(2-diethylamino-ethyl nicotinamide were given 1000 Gy of irradiation from 137cesium source (1.3 Gy/min., Scanditronix) at room temperature for 30 min. The various reaction mixtures were then vacuum evaporated to dryness, redissolved in methanol, spotted on silica gel 60 F245 thin layer chromatography (TLC) plates in 1-butanol:acetic acid:water (4:1:1, v/v/v), and visualized with short and long wave ultraviolet light and also in an iodine chamber, and the Rf values calculated in the conventional manner.
Reaction SMILES: C([O:3][C:4]([C@H:6]1[C@H:10]([CH2:11][N:12]([CH:29]([CH3:31])[CH3:30])[C:13](=[O:28])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH2:23][CH2:24][CH2:25][O:26][CH3:27])[CH:15]=2)[CH2:9][N:8]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:7]1)=[O:5])C.O[Li].O.Cl>CO.C(Cl)Cl>[C:35]([O:34][C:32]([N:8]1[CH2:9][C@@H:10]([CH2:11][N:12]([CH:29]([CH3:30])[CH3:31])[C:13](=[O:28])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH2:23][CH2:24][CH2:25][O:26][CH3:27])[CH:15]=2)[C@H:6]([C:4]([OH:5])=[O:3])[CH2:7]1)=[O:33])([CH3:36])([CH3:38])[CH3:37]
Reactant: CCOC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1CN(C(=O)c1ccc(OC)c(OCCCOC)c1)C(C)C
Agent: Cl
Agent: [Li]O
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2C(=O)O)C(C)C)ccc1OC
Reaction time: 8 h

Procedure:
To a solution of (3S*,4R*)-4-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (1.41 g, 2.63 mmol) in MeOH (25 mL) cooled at 0° C., 662 mg of LiOH.H2O is added. The reaction mixture is stirred overnight. The mixture is taken up in CH2Cl2, an aqueous HCl (5%) solution is added and the resulting mixture is extracted 3 times with CH2Cl2, dried over Na2SO4, filtered and concentrated. The crude material is used in the next step without purification. TLC, Rf (CH2Cl2/MeOH 95:5)=0.15. MS (LC-MS): 409.0 [M-H-Boc]−; tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 mumin): 4.96 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([NH2:11])[CH:5]=1.[Cl:13][C:14]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:15]=1[O:16][CH2:17][C:18](O)=O.ClCCl.[OH-].[Na+]>C[Si](OP(=O)=O)(C)C>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]2[O:10][C:18]([CH2:17][O:16][C:15]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:14]=3[Cl:13])=[N:11][C:6]=2[CH:5]=1)=[O:12]
Reactant: COC(=O)c1ccc(O)c(N)c1
Reactant: O=C(O)COc1ccc(Cl)cc1Cl
Agent: C[Si](C)(C)OP(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COC(=O)c1ccc2oc(COc3ccc(Cl)cc3Cl)nc2c1
Temperature: 160 °C
Yield: 72.6 %

Procedure:
A mixture of 3-amino-4-hydroxy-benzoic acid methyl ester (105.7 mg, 0.63 mmol) and 2,4-dichlorophenoxyacetic acid (100 mg, 0.45 mmol) in PPSE (1.5 mL) was heated at 160° C. for 4 h. At the end of the reaction period, the mixture was taken to 3 mL dichloromethane and neutralized with 4.5 mL 1 N NaOH solution. The organic layer was separated and the aqueous solution extracted with 3×3 mL portions of dichloromethane. The combined extracts were dried over anhydrous MgSO4, filtered and the solvent was removed with rotary evaporator under reduced pressure. The residue was purified by flash chromatography (EtOAc:hexanes=1:1) to afford 2-(2,4-dichlorophenoxymethyl)-benzoxazole-5-carboxylic acid methyl ester as a colorless powder (0.115 g, 52% yield).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[CH:14]=[C:13]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][C:18]=3[CH3:28])[C:12]([NH2:29])=[CH:11][CH:10]=2)=[N:3]1.[C:30]1(=[O:40])[C@@H:38]2[C@@H:33]([CH2:34][CH2:35][CH2:36][CH2:37]2)[C:32](=O)[O:31]1>>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:29]=[C:32]([C@H:33]4[CH2:34][CH2:35][CH2:36][CH2:37][C@H:38]4[C:30]([OH:40])=[O:31])[N:15]([CH2:16][C:17]4[CH:22]=[CH:21][C:20]([O:23][C:24]([F:25])([F:26])[F:27])=[CH:19][C:18]=4[CH3:28])[C:13]=3[CH:14]=2)=[N:3]1
Reactant: O=C1OC(=O)[C@@H]2CCCC[C@H]12
Reactant: Cc1cc(OC(F)(F)F)ccc1CNc1cc(OCc2ccn(C)n2)ccc1N
Product: Cc1cc(OC(F)(F)F)ccc1Cn1c([C@H]2CCCC[C@H]2C(=O)O)nc2ccc(OCc3ccn(C)n3)cc21

Procedure:
The title compound was prepared using analogous conditions described in Example 92 using 5-((1-methyl-1H-pyrazol-3-yl)methoxy)-N1-(2-methyl-4-(trifluoromethoxy)benzyl)benzene-1,2-diamine and cis-hexahydroisobenzofuran-1,3-dione in Step D. MS (ESI): mass calcd. for C28H29F3N4O4, 542.20; m/z found, 543.2 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 7.71 (d, J=7.7, 1H), 7.58 (d, J=2.2, 1H), 7.35 (s, 1H), 7.24 (s, 1H), 7.15 (s, 1H), 7.01 (d, J=10.0, 1H), 6.42 (d, J=8.8, 1H), 6.18 (d, J=2.2, 1H), 5.72-5.60 (m, 2H), 4.96 (s, 2H), 3.76 (s, 3H), 3.65 (s, 1H), 2.72 (s, 1H), 2.51 (s, 3H), 2.22-1.66 (m, 5H), 1.62-1.33 (m, 3H).
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([OH:5])=O.[NH2:32][CH2:33][C@@H:34]([OH:36])[CH3:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:29])([F:30])[F:31])[O:14][N:13]=2)=[CH:10][CH:11]=1)[C:3]([NH:32][CH2:33][C@@H:34]([OH:36])[CH3:35])=[O:5]
Reactant: C[C@H](O)CN
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: C[C@H](O)CNC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 44.3 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 30 mg, 0.070 mmol), (S)-(+)-1-amino-2-propanol (7.84 mg, 0.104 mmol), HATU (34.4 mg, 0.090 mmol), and 4-methylmorpholine (28.1 mg, 0.278 mmol) were dissolved in DMF (1 mL). After stirring 1 h, the mixture was purified by prep HPLC (PHENOMENEX® Luna 5u 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 10 min, 20 mL/min, 220 nM, product retention=11.8 min) to provide 2-hydroxy-N—((S)-2-hydroxypropyl)-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (19 mg, 0.031 mmol, 44.7% yield) as a mixture of diastereomers: LCMS=489.1 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.16 (2 H, d, J=8.35 Hz), 7.54-7.74 (7 H, m), 5.15 (1 H, s), 3.80-3.92 (1 H, m), 3.12-3.42 (2 H, m), 1.13 (3 H, d, J=4.83 Hz); HPLC peak RT=8.6 min (Method A).
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C([Sn](CCCC)(CCCC)[C:24]1[S:25][CH:26]=[CH:27][CH:28]=1)CCC>C(#N)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([C:24]4[S:25][CH:26]=[CH:27][CH:28]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Solvent: CC#N
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4cccs4)cc3CC[C@@H]12
Yield: 33.1 %

Procedure:
Five hundred mg of (4aR)-(10bR)-4,10b-dimethyl-8-bromo-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one was combined with 730 mg of 2-(tri-n-butylstannyl)thiophene and 100 mg of bis(triphenylphosphene)palladium chloride in 6 mL of acetonitrile in a screw capped sealable tube. The mixture was flushed with argon for 5 minutes, capped and heated at 90° for 20 h. Upon cooling, the mixture was filtered and the filtrate was concentrated in vacuum. The residue was purified by chromatography on a silica gel column, eluting with ethyl acetate, and the isolated product was recrystallized from ethyl acetate/hexane/chloroform to obtain 167 mg of the desired product. mp 193°-195°. FDMS 311.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]2[C:12]([C:15]([OH:17])=O)=[CH:13][N:14]=[C:8]2[CH:7]=1.C(Cl)(=O)C(Cl)=O.[CH2:24]([N:31]1[C:39]2[CH:38]=[CH:37][CH:36]=[C:35]([NH2:40])[C:34]=2[C:33]([CH:41]2[CH2:43][CH2:42]2)=[N:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C>ClCCl.CN(C)C=O>[CH2:24]([N:31]1[C:39]2[C:34](=[C:35]([NH:40][C:15]([C:12]3[N:9]4[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:7][C:8]4=[N:14][CH:13]=3)=[O:17])[CH:36]=[CH:37][CH:38]=2)[C:33]([CH:41]2[CH2:42][CH2:43]2)=[N:32]1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: Nc1cccc2c1c(C1CC1)nn2Cc1ccccc1
Reactant: COCCOc1ccn2c(C(=O)O)cnc2c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCOc1ccn2c(C(=O)Nc3cccc4c3c(C3CC3)nn4Cc3ccccc3)cnc2c1
Temperature: 25 °C
Yield: 29.1 %

Procedure:
To a magnetically stirred, ice cooled, suspension of 7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxylic acid (29.5 mg, 0.125 mmol) (prepared as in Example 1, steps A-D) in dichloromethane (1 mL) was added N,N-dimethylformamide (5 μL) followed by oxalyl chloride (79.7 μL, 0.159 mmol; 2M solution in dichloromethane). The mixture was stirred in a sealed vial and allowed to warm to ambient temperature. The vial was occasionally vented to allow gases to evolve. After 30 minutes a solution of 1-benzyl-3-cyclopropyl-1H-indazol-4-amine (35.0 mg, 0.133 mmol) in dichloromethane was added followed by triethylamine (27.8 μL; 0.199 mmol). The mixture was stirred for 24 hours and then concentrated under reduced pressure. The material was purified by preparative thin layer chromatography, eluting with 10% methanol in dichloromethane. Further purification was carried out eluting with hexane/ethyl acetate (3:1). The desired band was isolated and concentrated to give N-(1-benzyl-3-cyclopropyl-1H-indazol-4-yl)-7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxamide (17.5 mg). MS (APCI), positive scan, m/z=482.3 (M+H).
Reaction SMILES: Br[C:2]1[N:3]([CH2:7][C:8]2[CH:9]=[C:10]([C:14]3[CH:18]=[C:17]([CH2:19][CH:20]([CH3:22])[CH3:21])[S:16][C:15]=3[S:23]([NH:26][C:27]([CH3:30])([CH3:29])[CH3:28])(=[O:25])=[O:24])[CH:11]=[CH:12][CH:13]=2)[CH:4]=[CH:5][N:6]=1.C(O)C.[S:34]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35]1.[OH-].[Na+]>C1(C)C=CC=CC=1.CCOC(C)=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>[S:34]1[CH:38]=[CH:37][C:36]([C:2]2[N:3]([CH2:7][C:8]3[CH:9]=[C:10]([C:14]4[CH:18]=[C:17]([CH2:19][CH:20]([CH3:22])[CH3:21])[S:16][C:15]=4[S:23]([NH:26][C:27]([CH3:30])([CH3:29])[CH3:28])(=[O:25])=[O:24])[CH:11]=[CH:12][CH:13]=3)[CH:4]=[CH:5][N:6]=2)=[CH:35]1
Reactant: CC(C)Cc1cc(-c2cccc(Cn3ccnc3Br)c2)c(S(=O)(=O)NC(C)(C)C)s1
Reactant: OB(O)c1ccsc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(C)Cc1cc(-c2cccc(Cn3ccnc3-c3ccsc3)c2)c(S(=O)(=O)NC(C)(C)C)s1
Temperature: 90 °C
Reaction time: 4 h
Yield: 71 %

Procedure:
To a solution of 3-[3-(2-bromoimidazol-1-ylmethyl)phenyl]-5-iso-butyl-N-tert-butylthiophene-2-sulfonamide (61.7 mg, 0.121 mmol; see Example 11((b)) in toluene (5 mL) and ethanol (0.5 mL) was added 3-thienyl boronic acid (77.3 mg, 0.604 mmol), Pd(PPh3)4 (8.4 mg, 7.25 μmol) and NaOH (0.48 mL, 0.725 mmol, 1.5 M aq), and the reaction mixture stirred for 4 h at 90° C. Another portion of 3-thienyl boronic acid (60.0 mg, 0.469 mmol) and Pd(PPh3)4 (5.0 mg, 4.3 μmol) was added and the reaction was stirred overnight at 90° C. The reaction mixture was diluted with EtOAc (30 mL) and washed with water, dried (over anhydrous MgSO4), concentrated in vacuo, and the residue purified by flash chromatography using EtOAc:hexane (8:2 to 9:1) as eluent to give the sub-title compound in 71% yield (44.3 mg, 0.0862 mmol).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9](=[O:14])[CH:10]=[C:11]([CH3:13])[CH3:12])[CH:5]=[CH:6][C:7]=1[CH3:8].ClC1C=CC=C(C(OO)=[O:23])C=1.O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:9]([CH:10]2[C:11]([CH3:12])([CH3:13])[O:23]2)=[O:14])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)=CC(=O)c1ccc(C)c(Br)c1
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(C(=O)C2OC2(C)C)cc1Br
Temperature: 25 °C
Yield: 100.4 %

Procedure:
To a cooled solution (at 0° C.) of 1-(3-bromo-4-methylphenyl)-3-methylbut-2-en-1-one (1.50 g, 5.92 mmol, 1.0 eq) in DCM (100 mL), m-chloroperbenzoic acid (77%, 4.30 g, 17.78 mmol, 3.0 eq) was added portion wise and then allowed to warm to room temperature. After stirring for 12 h at room temperature water was added to the reaction mixture and the layers were separated. The organic layer was washed with saturated aqueous solution of sodium bicarbonate (3×50 mL) followed by brine (50 mL) and then dried (Na2SO4) and filtered. The filtrate was concentrated under vacuum. The crude product was purified by flash column chromatography (silica gel, 5% ethyl acetate in hexane) to afford 1.60 g of the desired product, as a white solid. 1HNMR (400 MHz, CDCl3) δ 8.13 (d, J=1.5 Hz, 1H), 7.81 (dd, J=1.5, 8.0 Hz, 1H), 7.36 (d, J=8.0 Hz, 1H), 3.99 (s, 1H), 2.47 (s, 3H), 1.58 (s, 3H), 1.23 (s, 3H); ESI-MS (m/z) 269, 271 [(MH)+, Br79,81].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8]Cl)[CH:5]=[CH:4][N:3]=1.[OH:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.CO.C(Cl)Cl.O>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][O:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[CH:13][CH:12]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)c2ccccc12
Reactant: ClCc1ccnc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1ccc(OCc2ccnc(Cl)c2)c2ccccc12
Temperature: 55 °C
Reaction time: 24 h
Yield: 72.6 %

Procedure:
To a mixture of 2-chloro-4-(chloromethyl)pyridine (30 g, 185 mmol) and tert-butyl (4-hydroxynaphthalen-1-yl)carbamate (40.0 g, 154 mmol) in acetonitrile (200 mL) was added caesium carbonate (75 g, 231 mmol) and the resulting mixture was heated to 55° C. After 16 h the reaction mixture was diluted with 30% MeOH in DCM (600 mL) and water (400 mL). The layers were separated and the aqueous layer was extracted with a further amount of 30% MeOH in DCM (2×600 mL) and the organics were concentrated in vacuo to afford the crude product. The crude product was triturated with MeOH (200 mL), sonicated for c.a. 5 min and slurried for 1 day. The resulting solid was collected by filtration and washed with MeOH (2×10 mL) to yield the subtitle compound tert-butyl (4-((2-chloropyridin-4-yl)methoxy)naphthalen-1-yl)carbamate as a yellow solid (43 g, 70%); Rt 2.60 min (Method 1); m/z 383 (M−H)− (ES−); 1H NMR δ:1.47 (9H, s), 5.41 (2H, s), 6.98 (1H, d), 7.36 (1H, d), 7.55-7.61 (3H, overlapping m), 7.65 (1H, m), 7.94 (1H, m), 8.29 (1H, m), 8.45 (1H, m), 9.00 (1H, bs).
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]1[C:9]([NH:10][C:11]2[C:16]3[CH2:17][C:18]([CH3:21])([CH3:20])[CH2:19][C:15]=3[N:14]=[C:13]([C:22]3[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=3[F:29])[N:12]=2)=[CH:8][CH:7]=[N:6][CH:5]=1.[OH-].[Na+].Cl>O1CCOCC1>[Cl:28][C:26]1[CH:25]=[CH:24][C:23]([F:29])=[C:22]([C:13]2[N:12]=[C:11]([NH:10][C:9]3[C:4]([C:3]([OH:30])=[O:2])=[CH:5][N:6]=[CH:7][CH:8]=3)[C:16]3[CH2:17][C:18]([CH3:20])([CH3:21])[CH2:19][C:15]=3[N:14]=2)[CH:27]=1
Reactant: COC(=O)c1cnccc1Nc1nc(-c2cc(Cl)ccc2F)nc2c1CC(C)(C)C2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC1(C)Cc2nc(-c3cc(Cl)ccc3F)nc(Nc3ccncc3C(=O)O)c2C1
Temperature: 60 °C
Yield: 79 %

Procedure:
To a solution of 4-[2-(5-Chloro-2-fluoro-phenyl)-6,6-dimethyl-6,7-dihydro-5H-cyclopentapyrimidin-4-ylamino]-nicotinic acid methyl ester (178 mg, 0.42 mmol) in dioxane (10 mL) was added NaOH (aq.) (451 μL, 0.44 mmol, 0.97N solution). The mixture was heated at 60° C. for 1 h then cooled, and HCl (aq.) (425 μL, 0.44 mmol, 1.03N solution) was added. On addition, the acid precipitated from solution and was filtered and dried in vacuo, to give 137 mg of product.