Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:25])=[C:11]([N:14]4[CH2:21][C:20](=[N:22][O:23][CH3:24])[C:16]5([CH2:19][NH:18][CH2:17]5)[CH2:15]4)[N:12]=3)[C:7](=[O:26])[C:6]([C:27]([OH:29])=[O:28])=[CH:5]2)[CH2:3][CH2:2]1.[CH2:30](O)C.C([BH3-])#N.[Na+]>C(O)(=O)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:25])=[C:11]([N:14]4[CH2:21][C:20](=[N:22][O:23][CH3:24])[C:16]5([CH2:19][N:18]([CH3:30])[CH2:17]5)[CH2:15]4)[N:12]=3)[C:7](=[O:26])[C:6]([C:27]([OH:29])=[O:28])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCO
Reactant: CON=C1CN(c2nc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CC12CNC2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: CON=C1CN(c2nc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CC12CN(C)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.7 %

Procedure:
300 mg of 1-Cyclopropyl-6-fluoro-7-[8-(methoxyimino)-2,6-diazaspiro[3,4]oct-6-yl]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid was added to 10 ml of ethanol, and thereto 0.2 ml of acetic acid was dropped and 42 mg of p-formaldehyde was added. The mixture was stirred at room temperature for 30 minutes, and thereto 85 mg of sodium cyanoborohydride was added. It was stirred at room temperature for 2 hours. The resulting precipitate was filtered and dried to give 260 mg of the titled compound(yield: 83.7%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:10][CH2:9][CH2:8][C:7]1=[O:11].[F:12][C:13]([F:27])([F:26])[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:34]([OH:41])(=[O:40])/[CH:35]=[CH:36]/[C:37]([OH:39])=[O:38]>C(O)CCC.C(O)C>[C:34]([OH:41])(=[O:40])/[CH:35]=[CH:36]/[C:37]([OH:39])=[O:38].[F:26][C:13]([F:12])([F:27])[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([N:20]2[CH2:21][CH2:22][N:23]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[CH2:10][CH2:9][CH2:8][C:7]3=[O:11])[CH2:24][CH2:25]2)[CH:15]=1
Reactant: O=C1CCCN1CCCCBr
Reactant: FC(F)(F)c1ccnc(N2CCNCC2)c1
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCCCO
Product: O=C1CCCN1CCCCN1CCN(c2cc(C(F)(F)F)ccn2)CC1
Yield: 52 %

Procedure:
2 7 g of 1-(4-bromobutyl)-2-pyrrolidinone were mixed with 2.2 g of 1-[4-(trifluoromethyl)-2-pyridinyl]piperazine dissolved in 30 ml of butanol, after which 1.3 g of sodium carbonate were added. The mixture was refluxed for 2 hours, after which the precipitate was filtered and washed with butanol. The solvent was evaporated and the residue was dissolved in dichloromethane, washed with water, and dried over anhydrous magnesium sulfate. After evaporation of the solvent 3.4 g of 1-[4-[4-[4-(trifluoromethyl)-2-pyridinyl]-1-piperazinyl]butyl]-2-pyrrolidinone were obtained. To make the monofumarate, 1 g of fumaric acid dissolved in absolute ethanol was mixed with the free base. The resulting compound was recrystallized twice from acetonitrile, after which 2.4 g (52% yield) of 1-[4-[4-[4-(trifluoromethyl)-2-pyridinyl]-1-piperazinyl]butyl]-2pyrrolidinone (E)-2-butenedioate (1:1) salt were obtained with a melting point of 140° C.
Reaction SMILES: [C:1](#[N:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[CH2:10]([O:12][P:13]([CH2:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1)([O:15][CH2:16][CH3:17])=[O:14])[CH3:11]>N1C=CC=CC=1.ClCCl>[C:1]([C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:23]([C:22]1[CH:26]=[CH:27][C:19]([CH2:18][P:13](=[O:14])([O:12][CH2:10][CH3:11])[O:15][CH2:16][CH3:17])=[CH:20][CH:21]=1)=[O:24])#[N:9]
Reactant: N#Cc1ccccc1N
Reactant: CCOP(=O)(Cc1ccc(C(=O)Cl)cc1)OCC
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOP(=O)(Cc1ccc(C(=O)Nc2ccccc2C#N)cc1)OCC
Reaction time: 12 h

Procedure:
A 15.7 g portion of anthranilonitrile was dissolved in 50 ml of pyridine. While the solution was stirred under ice-cooling, a solution of 40.7 g of 4-[(diethoxyphosphoryl)-methyl]benzoyl chloride in 50 ml of dry dichloromethane was added dropwise. The stirring was continued at room temperature for 12 hours, after which the reaction mixture was diluted with 200 ml of dichloromethane and washed with diluted hydrochloric acid. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was recrystallized from chloroform-n-hexane to provide 25.9 g of diethyl 4-[N-(2-cyanophenyl)carbamoyl]benzyl-phosphonate as colorless crystals.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[C:13]([C:15]3[CH:24]=[C:23]4[C:18]([CH2:19][CH2:20][NH:21][CH2:22]4)=[CH:17][CH:16]=3)[N:12]=[C:11]([NH2:25])[N:10]=2)[CH2:5][CH2:4]1.F[C:27]1[N:32]=[CH:31][C:30]([C:33]2[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[CH:35][CH:34]=2)=[CH:29][CH:28]=1>>[NH2:25][C:11]1[N:12]=[C:13]([C:15]2[CH:24]=[C:23]3[C:18]([CH2:19][CH2:20][N:21]([C:27]4[N:32]=[CH:31][C:30]([C:33]5[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[CH:35][CH:34]=5)=[CH:29][CH:28]=4)[CH2:22]3)=[CH:17][CH:16]=2)[CH:14]=[C:9]([N:6]2[CH2:5][CH2:4][N:3]([CH3:2])[CH2:8][CH2:7]2)[N:10]=1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Reactant: N#Cc1ccc(-c2ccc(F)nc2)cc1
Agent: Cl
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(c3ccc(-c5ccc(C#N)cc5)cn3)CC4)nc(N)n2)CC1

Procedure:
This compound was prepared from 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt and 4-(6-fluoropyridin-3-yl)benzonitrile using procedures analogous to those for Example 14. Analytic LCMS (M+H)+: m/z=503.4.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:13]([OH:15])=O)[CH:10]([CH3:12])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH2:16][CH:17]([CH:25]([OH:52])[CH:26]([NH:34][C:35](=[O:51])[C@H:36]([CH:48]([CH3:50])[CH3:49])[NH:37][C:38]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.N=C=N.CO>C(Cl)(Cl)Cl>[C:1]([NH:8][C@H:9]([C:13]([NH:16][CH:17]([CH:25]([OH:52])[CH:26]([NH:34][C:35](=[O:51])[C@H:36]([CH:48]([CH3:50])[CH3:49])[NH:37][C:38]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:15])[CH:10]([CH3:11])[CH3:12])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)NC(Cc1ccccc1)C(O)C(N)Cc1ccccc1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: N=C=N
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)NC(Cc1ccccc1)C(O)C(Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C

Procedure:
Boc-valine was coupled to the resultant compound of Example 69 using the carbodiimide coupling procedure of Example 55 to provide, after silica gel chromatography using 3% methanol in chloroform, the desired compound (82%, Rf 0.7, 10% methanol in chloroform) as a white solid, m.p. 184°-184° C. Mass spectrum: (M+H)+ =703.
Reaction SMILES: CN(C)C=O.Cl[CH2:7][CH2:8][O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([O:20][C:21]3[C:22]([CH3:31])=[N:23][C:24]4[C:29]([CH:30]=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:32][CH3:33].C(=O)([O-])[O-].[K+].[K+].[NH:40]1[CH2:45][CH2:44][CH2:43][CH:42]([CH2:46][OH:47])[CH2:41]1>O>[CH3:33][O:32][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:10]=1[O:9][CH2:8][CH2:7][N:40]1[CH2:45][CH2:44][CH2:43][CH:42]([CH2:46][OH:47])[CH2:41]1)[N:17]=[CH:16][CH:15]=[C:14]2[O:20][C:21]1[C:22]([CH3:31])=[N:23][C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[CH:26][CH:25]=2
Reactant: OCC1CCCNC1
Reactant: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCCN1CCCC(CO)C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
N,N-Dimethylformamide (1 ml) was added to 7-(2-chloro-ethoxy)-6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinoline (compound 353) (50 mg), potassium carbonate (53 mg), and piperidin-3-yl-methanol (44 mg), and the mixture was stirred at 80° C. overnight. The reaction solution was then stirred at 100° C. for one day, and the reaction solution was cooled to room temperature. Water was added thereto, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (33 mg, yield 55%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([NH:13][C:14]2[NH:15][C:16]3[C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)=[O:12])[N:2]=1.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.[C:59]([O:63][C:64]([N:66]1[CH2:71][CH2:70][C:69]2[N:72]=[C:73]([NH2:75])[S:74][C:68]=2[CH2:67]1)=[O:65])([CH3:62])([CH3:61])[CH3:60]>CN(C=O)C>[C:59]([O:63][C:64]([N:66]1[CH2:71][CH2:70][C:69]2[N:72]=[C:73]([NH:75][C:23]([C:22]3[C:16]4[NH:15][C:14]([NH:13][C:11]([C:3]5[N:2]=[CH:1][C:10]6[C:5]([CH:4]=5)=[CH:6][CH:7]=[CH:8][CH:9]=6)=[O:12])=[N:18][C:17]=4[CH:19]=[CH:20][CH:21]=3)=[O:24])[S:74][C:68]=2[CH2:67]1)=[O:65])([CH3:62])([CH3:60])[CH3:61]
Reactant: CC(C)(C)OC(=O)N1CCc2nc(N)sc2C1
Reactant: O=C(Nc1nc2cccc(C(=O)O)c2[nH]1)c1cc2ccccc2cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCc2nc(NC(=O)c3cccc4nc(NC(=O)c5cc6ccccc6cn5)[nH]c34)sc2C1
Temperature: 80 °C
Reaction time: 0.08 h
Yield: 49.8 %

Procedure:
To a solution of 0.25 g (0.75 mmol) of 2-[(isoquinoline-3-carbonyl)-amino]-3H-benzoimidazole-4-carboxylic acid in DMF (4 mL) was added 0.4 g (1.05 mmol) of HBTU and DIEA (1 mL). The mixture was stirred for 5 min and then 0.18 g (0.7 μmmol) of 2-amino-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic acid tert-butyl ester was added. The resulting reaction mixture was heated at 80° C. for 2 h. After usual workup, the residue was purified by column chromatography to afford the 0.2 g (55%) of 2-({2-[(isoquinoline-3-carbonyl)-amino]-3H-benzoimidazole-4-carbonyl}-amino)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic acid tert-butyl ester. LCMS: 570 (M+1)+. 1H NMR (DMSO-d6, 400 MHz): δ 9.56 (s, 1H), 8.84 (s, 1H), 8.35 (m, 2H), 7.96 (m, 4H), 7.84 (d, 1H), 7.35 (t, 1H), 4.58 (bs, 2H), 3.70 (t, 2H), 2.73 (t, 2H), 1.44 (s, 9H) ppm.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1/[CH:10]=[CH:11]/[C:12](/[CH3:21])=[CH:13]/[CH:14]=[CH:15]/[C:16](/[CH3:20])=[CH:17]/[CH2:18][OH:19].[CH3:22][C:23]([C:25]([O:27]C)=O)=C>O.C(OCC)(=O)C>[CH3:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:3][CH2:2][CH2:7][CH2:6][CH2:22][CH2:23][C:25]([O:19][CH2:18]/[CH:17]=[C:16](/[CH:15]=[CH:14]/[CH:13]=[C:12](/[CH:11]=[CH:10]/[C:3]1[C:4]([CH3:8])([CH3:9])[CH2:5][CH2:6][CH2:7][C:2]=1[CH3:1])\[CH3:21])\[CH3:20])=[O:27]
Reactant: C=C(C)C(=O)OC
Reactant: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/CO)C(C)(C)CCC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCCC(=O)OC/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CCCC1(C)C

Procedure:
An aqueous phase was prepared by dissolving 0.5 g of poly(vinyl alcohol) in 50 ml water saturated by 6 ml of ethyl acetate. An organic phase was prepared by dissolving 0.075 g retinol palmitate, 0.1 g mineral oil, 0.01 g of an antioxidant (chosen from BHA, BHT, tocopherol or their mixture) and 0.815 g PMMA in 5 ml of ethyl acetate. The organic phase was poured into the aqueous phase while stirring and then 100 ml of fresh water were added. The microcapsules formed were filtered, washed by water and dried at the temperature no higher 20° C. An average diameter of the microcapsules was 40 μm.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[O:28]1[CH2:31][CH:30]([CH2:32][C:33](OC)=[O:34])[CH2:29]1>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:33](=[O:34])[CH2:32][CH:30]5[CH2:31][O:28][CH2:29]5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Reactant: COC(=O)CC1COC1
Agent: Cl
Product: O=C(CC1COC1)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1

Procedure:
The title compound, white solid (91 mg, 85%), MS (ISP) m/z=429.3 [(M+H)+], mp 175° C., was prepared in accordance with the general method of example 5 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and methyl 2-oxetan-3-yl-acetate.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][CH2:19][CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:13]=[N:12]2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:25][C:26]1[CH:30]=[CH:29][N:28]([CH2:31][C:32]([CH3:35])([OH:34])[CH3:33])[N:27]=1>>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][CH2:19][CH:20]3[CH2:21][CH2:22][CH2:23][CH2:24]3)[CH:13]=[N:12]2)[C:8]([NH:25][C:26]2[CH:30]=[CH:29][N:28]([CH2:31][C:32]([OH:34])([CH3:33])[CH3:35])[N:27]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(O)Cn1ccc(N)n1
Reactant: O=C(O)C(CC1CCCC1)n1ncc(OCC2CCCC2)cc1=O
Product: CC(C)(O)Cn1ccc(NC(=O)C(CC2CCCC2)n2ncc(OCC3CCCC3)cc2=O)n1
Yield: 10 %

Procedure:
Using the method described in Example 1, 3-cyclopentyl-2-(4-cyclopentylmethoxy-6-oxo-6H-pyridazin-1-yl)-propionic acid (Intermediate 59) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1) afforded 3-cyclopentyl-2-(4-cyclopentylmethoxy-6-oxo-6H-pyridazin-1-yl)-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide as a white solid (22.2 mg, 10%); ES+-HRMS m/e calcd for C25H37N5O4 [M+H+] 472.2919, found 472.2922. 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.05 (s, 3H), 1.06 (s, 3H), 1.05 (m, 1H), 1.25-1.97 (m, 18H), 2.26 (m, 1H), 3.89 (s, 2H), 3.90 (d, J=5.8 Hz, 2H), 4.67 (s, 1H), 5.46 (dd, J=4.2, J=11.2 Hz, 1H), 6.27 (d, J=2.8 Hz, 1H), 6.39 (d, J=2.2 Hz, 1H), 7.52 (d, J=2.2 Hz, 1H), 7.82 (d, J=2.8 Hz, 1H), 10.73 (s, 1H).
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[O:13][C:12]([CH2:14]O)=[CH:11][CH:10]=2)[O:8][CH2:7][CH2:6][O:5]1.CCN(CC)CC.C(Cl)[Cl:24]>CN(C1C=CN=CC=1)C>[Cl:24][CH2:14][C:12]1[O:13][C:9]([C:4]2([CH3:3])[O:8][CH2:7][CH2:6][O:5]2)=[CH:10][CH:11]=1
Reactant: CC1(c2ccc(CO)o2)OCCO1
Reactant: ClCCl
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: CCN(CC)CC
Product: CC1(c2ccc(CCl)o2)OCCO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-yl]-methanol (3.20 g, 17.37 mmol) in dry CH2Cl2 (32.0 mL) was treated at 0° C. with Et3N (3.14 mL, 22.59 mmol) followed by DMAP (212 mg, 1.74 mmol) and Ms-C1 (1.62 mL, 20.85 mmol). After stirring at rt for 2 h, the reaction mixture was quenched with water (30 mL), extracted with CH2Cl2 (30 mL) and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give 4.49 g of crude 2-(5-chloromethyl-furan-2-yl)-2-methyl-[1,3]dioxolane as an brown oil. The crude material in acetone (43 mL) was treated, under inert atmosphere (N2) with 4-nitro-2H-[1,2,3]triazole (1.97 g, 17.27 mmol), K2CO3 (7.16 g, 51.82 mmol) followed by TBA bromide (1.11 g, 3.45 mmol). The reaction mixture was stirred for 2 days at rt. Water (30 mL), followed by EA (40 mL) was added. The aq. layer was extracted with EA (40 mL) and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (60:40 hept-EA) gave the title compound as an orange oil: TLC:rf (60:40 hept-EA)=0.28. LC-MS-conditions 02: tR=0.95 min; [M+H]+=281.01.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[F:19][C:20]([F:33])([F:32])[O:21][C:22]1[CH:23]=[C:24]([CH2:28][C:29](O)=[O:30])[CH:25]=[CH:26][CH:27]=1>>[N:12]1([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:18])[N:2]([NH:1][C:29](=[O:30])[CH2:28][C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([O:21][C:20]([F:32])([F:19])[F:33])[CH:23]=3)[N:11]=2)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: O=C(O)Cc1cccc(OC(F)(F)F)c1
Reactant: Nn1nc(N2CCOCC2)c2ccccc2c1=O
Product: O=C(Cc1cccc(OC(F)(F)F)c1)Nn1nc(N2CCOCC2)c2ccccc2c1=O

Procedure:
The product of Example 1B and 2-[3-(trifluoromethoxy)phenyl]acetic acid were treated using a method similar to that described in Example 111 to give the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ 8.31 (d, J=7.7, 1H), 8.04 (d, J=7.8, 1H), 8.02-7.96 (m, 1H), 7.94-7.88 (m, 1H), 7.51 (t, J=7.9, 1H), 7.45-7.37 (m, 2H), 7.29 (d, J=8.2, 1H), 3.85-3.79 (m, 4H), 3.76 (s, 2H), 3.14-3.05 (m, 4H); MS (ESI−) M/Z 447 (M−H)−.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:11]2[NH:30][C:14]3[C:15]([Cl:29])=[N:16][C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]([F:28])([F:27])[F:26])=[CH:18][C:13]=3[N:12]=2)[N:8]([CH3:10])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].C(Cl)[Cl:32]>CO>[C:1]([C:5]1[C:6]([Cl:32])=[C:7]([C:11]2[NH:30][C:14]3[C:15]([Cl:29])=[N:16][C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]([F:27])([F:28])[F:26])=[CH:18][C:13]=3[N:12]=2)[N:8]([CH3:10])[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1nc(C(C)(C)C)cc1-c1nc2cc(-c3ccccc3C(F)(F)F)nc(Cl)c2[nH]1
Reactant: ClCCl
Solvent: CO
Product: Cn1nc(C(C)(C)C)c(Cl)c1-c1nc2cc(-c3ccccc3C(F)(F)F)nc(Cl)c2[nH]1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A solution of 2-(5-tert-butyl-2-methyl-2H-pyrazol-3-yl)-4-chloro-6-(2-trifluoromethyl-phenyl)-3H-imidazo[4,5-c]pyridine (101 mg, 0.232 mmol, Compound #74 freebase prepared according to Example 16, STEPS A, B and C) in DCM (2 mL) was treated with SO2Cl2 (28.3 μL, 0.348 mmol) and the resulting mixture was stirred at room temperature for 14 h. The resulting mixture was then diluted with MeOH (3 mL) and the solvent was removed under reduced pressure. The residue was chromatographed on a 25-g SiO2 pre-packed column eluting with 0:1-3:7 EtOAc/hexanes to yield 2-(5-tert-butyl-4-chloro-2-methyl-2H-pyrazol-3-yl)-4-chloro-6-(2-trifluoromethyl-phenyl)-3H-imidazo[4,5-c]pyridine. 1H-NMR (400 MHz, CD3OD) δ: 7.84 (d, J=7.8 Hz, 1H), 7.69-7.76 (m, 1H), 7.68 (s, 1H), 7.62-7.67 (m, 1H), 7.59 (d, J=7.6 Hz, 1H), 4.14 (s, 3H), 1.45 (s, 9H). Mass Spectrum (LCMS, ESI pos.): Calculated for C21H18Cl2F3N5: 468.1 (M+H). Measured: 468.1.
Reaction SMILES: CS(C)=O.[F:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[H-].[Na+].[N+]([C:18]1[O:22][C:21]([CH:23]=[O:24])=[CH:20][CH:19]=1)([O-])=O>O>[F:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:18]2[O:22][C:21]([CH:23]=[O:24])=[CH:20][CH:19]=2)=[CH:8][CH:7]=1
Reactant: Oc1ccc(F)cc1
Reactant: O=Cc1ccc([N+](=O)[O-])o1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=Cc1ccc(Oc2ccc(F)cc2)o1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 24.2 %

Procedure:
To a solution of DMSO (50 mL) of p-fluorophenol (3.6 g) was added NaH (1.3 g/60% in oil) at room temperature, which was stirred for 15 minutes at room temperature. 5-Nitro-furan-2-carbaldehyde (5.0 g) was then added thereto, which was stirred for 40 minutes at room temperature. Water was added to the reaction solution, which was then extracted with ethyl acetate. The solvent was evaporated from the organic layer under a reduced pressure, and the residue was purified by silica gel chromatography (heptane:ethyl acetate=2:1) to obtain 5-(4-fluoro-phenoxy)-furan-2-carbaldehyde (1.6 g).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=[CH:4][N:3]=1.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.[NH2:44][C:45]1[CH:65]=[CH:64][C:48]([O:49][C:50]2[C:55]([C:56]3[CH:61]=[CH:60][N:59]=[C:58]([NH:62][CH3:63])[N:57]=3)=[CH:54][CH:53]=[CH:52][N:51]=2)=[CH:47][CH:46]=1>C(Cl)(Cl)Cl>[F:1][C:2]1[N:3]=[CH:4][CH:5]=[CH:6][C:7]=1[C:8]([NH:44][C:45]1[CH:46]=[CH:47][C:48]([O:49][C:50]2[C:55]([C:56]3[CH:61]=[CH:60][N:59]=[C:58]([NH:62][CH3:63])[N:57]=3)=[CH:54][CH:53]=[CH:52][N:51]=2)=[CH:64][CH:65]=1)=[O:10]
Reactant: CNc1nccc(-c2cccnc2Oc2ccc(N)cc2)n1
Reactant: O=C(O)c1cccnc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CNc1nccc(-c2cccnc2Oc2ccc(NC(=O)c3cccnc3F)cc2)n1
Reaction time: 16 h

Procedure:
To a mixture of 2-fluoro-3-pyridinecarboxylic acid (1.06 g, 7.50 mmol) and HATU (3.11 g, 8.18 mmol) in CHCl3 at ambient temperature under nitrogen was added n,n-diisopropylethylamine (2.38 ml, 13.6 mmol) via syringe. The mixture was allowed to stir for 5 min, at which point 4-(2-(4-aminophenoxy)pyridin-3-yl)-N-methylpyrimidin-2-amine (2.00 g, 6.82 mmol) was added. The reaction was allowed to stir 16 h, resulting in the formation of a fine precipitate. The reaction was filtered, rinsing with 2× dichloromethane and the solid dried in vacuo to give 2-fluoro-N-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)nicotinamide as a tan solid. MS m/z=417 [M+1]+. Calc'd for C22H17FN6O2: 416.41.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=1[OH:15])[C:8]([O:10][CH3:11])=[O:9])#[N:4].BrCCO[Si]([C:23](C)([CH3:25])[CH3:24])(C)C>CN(C=O)C.CCOC(C)=O>[C:3]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=1[O:15][CH:23]([CH3:25])[CH3:24])[C:8]([O:10][CH3:11])=[O:9])#[N:4]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: COC(=O)c1ccc(O)c(C#N)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(OC(C)C)c(C#N)c1
Reaction time: 1.5 h
Yield: 84.2 %

Procedure:
To a suspension of NaH (0.39 g, 9.3 mmol) in DMF (15 mL) was added a solution of 3 (1.9 g, 6.5 mmol) in DMF (10 mL) at 0° C. under nitrogen. The reaction was stirred for 1.5 h, and then (2-bromoethoxy)-tert-butyldimethylsilane (2.09 mL, 9.7 mmol) was added. The reaction mixture was stirred overnight, diluted with EtOAc, quenched with aqueous ammonium chloride solution, and extracted with EtOAc (3×50 mL). The organic layers were combined and dried over Na2SO4. Purification with over silica gel (EtOAc) gave the product 4 (1.2 g, 41%) as a light yellow solid.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:8]1[O:10][C@@H:9]1[CH2:11]OS(C1C=C([N+]([O-])=O)C=CC=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[O:7]([CH2:11][C@@H:9]1[CH2:8][O:10]1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: c1ccc(OC[C@@H]2CO2)cc1
Temperature: 25 °C
Yield: 99.9 %

Procedure:
A solution of phenol (9.4 g, 100 mmol) and (2S)-(+)glycidyl 3-nitrobenzenesulfonate (25.9 g, 100 mmol) in 500 mL of acetone was treated with 3 equivalents of potassium carbonate (41.5 g, 300 mmol) and stirred at reflux for 1 day. The suspension was cooled to ambient temperature; the solid was filtered; and the filtrate was concentrated to dryness. The residue was partitioned between methylene chloride and water. The aqueous layer was extracted with CH2Cl2. The organic layers were combined and dried over MgSO4 and concentrated to give the title compound (15.0 g, 99%) as an orange oil; 1H NMR (300 MHz, CDCl3) δ 2.76 (dd, J=4.9, 2.6 Hz, 1 H), 2.90 (dd, J=4.9, 4.9 Hz, 1 H), 3.30–3.40 (m, 1 H), 3.95 (dd, J=11.0, 5.4 Hz, 1 H), 4.18 (dd, J=11.0, 3.0 Hz, 1 H), 6.85–7.00 (m, 3 H), 7.25–7.35 (m, 2 H); MS (ES) m/z: 151.0 (MH+).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C@H:4](/[CH:5]=[CH:6]/[C:7]([O:9][CH3:10])=[O:8])[C@H:3]1[C:11](Cl)=[O:12].[CH2:15]([OH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:14])[C@H:4](/[CH:5]=[CH:6]/[C:7]([O:9][CH3:10])=[O:8])[C@H:3]1[C:11]([O:22][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:12]
Reactant: COC(=O)/C=C/[C@@H]1[C@@H](C(=O)Cl)C1(C)C
Reactant: OCc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: c1ccccc1
Product: COC(=O)/C=C/[C@@H]1[C@@H](C(=O)OCc2ccccc2)C1(C)C

Procedure:
Using the procedure of Example 3, 12.5 ml of 1 M/l of (1R,trans) 2,2-dimethyl-3-[(E)-3-methoxy-3-oxo-1-propenyl]-cyclopropane-1-carboxylic acid chloride in benzene and 1.35 ml of benzyl alcohol were reacted to obtain 1.77 g of benzyl (1R,trans) 2,2-dimethyl-3[(E)-3-methoxy-3-oxo-1-propenyl]-cyclopropane-1-carboxylate with a specific rotation of [α]D20 =+47.5°±1.5° (c=1% in chloroform).