Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:14][CH2:13][CH:12]([C:15]([NH:17][C:18]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:19]=2[C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][N:24]=2)=[O:21])=[O:16])[CH2:11][CH2:10]1)=O)(C)(C)C>C(O)(C(F)(F)F)=O>[NH2:8][CH:9]1[CH2:14][CH2:13][CH:12]([C:15]([NH:17][C:18]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:19]=2[C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][N:24]=2)=[O:21])=[O:16])[CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)NC1CCC(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)CC1
Solvent: O=C(O)C(F)(F)F
Product: NC1CCC(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)CC1
Reaction time: 0.08 h
Yield: 79.9 %

Procedure:
2-[[4-(tert-Butoxycarbonylamino)cyclohexylcarbonyl]-amino]-5-chloro-N-(5-chloropyridin-2-yl)benzamide (2.90 g, 5.71 mmol) was dissolved in TFA (10 mL). After 5 minutes, the reaction was concentrated in vacuo. The residue was diluted with methylene chloride and methanol. The organics were washed with saturated aqueous sodium carbonate (2×50 mL) and water (50 mL). The organic layer was dried over sodium sulfate, filtered and concetrated to give the title product (1.86 g, 4.56 mmol, 80%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[C:10]([F:14])=[CH:9][C:3]=1[C:4]([O:6]CC)=O.[C:15](#[N:17])[CH3:16].[H-].[Na+].CCOCC>O1CCCC1>[Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[C:10]([F:14])=[CH:9][C:3]=1[C:4]([CH2:16][C:15]#[N:17])=[O:6]
Reactant: CC#N
Reactant: CCOC(=O)c1cc(F)c(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: N#CCC(=O)c1cc(F)c(Cl)cc1Cl
Temperature: 25 °C
Yield: 34.5 %

Procedure:
A mixture of 47.4 g of ethyl 2,4-dichloro-5-fluoro-benzoate and 8.2 g of anhydrous acetonitrile are added dropwise to a suspension of 6.1 g of 80% strength sodium hydride in 100 ml of anhydrous tetrahydrofuran under reflux in the course of about 1 hour. The mixture is heated at the boiling point under reflux for a further hour and cooled to room temperature, and 150 ml of ether are added. The precipitate is filtered off with suction and dissolved in 50 ml of ice-water and the solution is acidified to pH=6 with 10% strength hydrochloric acid. The precipitate is filtered off cold with suction, rinsed with ice-water and dried in vacuo at 40° C. 16 g of 2,4-dichloro-5-fluoro-benzoylacetonitrile of melting point 96°-98° C. are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH2:30][CH:31]([F:33])[F:32])=[C:6]([C:8]2[C:9]3[N:10]([N:14]=[C:15]([NH:17][C:18]4[CH:28]=[CH:27][C:21]5[CH2:22][CH2:23][NH:24][CH2:25][CH2:26][C:20]=5[CH:19]=4)[N:16]=3)[CH:11]=[CH:12][CH:13]=2)[CH:7]=1.C(N(CC)CC)C.[CH3:41][N:42]([CH3:46])[C:43](Cl)=[O:44]>ClCCl.CN(C)C1C=CN=CC=1>[CH3:41][N:42]([CH3:46])[C:43]([N:24]1[CH2:23][CH2:22][C:21]2[CH:27]=[CH:28][C:18]([NH:17][C:15]3[N:16]=[C:9]4[C:8]([C:6]5[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=5[O:29][CH2:30][CH:31]([F:33])[F:32])=[CH:13][CH:12]=[CH:11][N:10]4[N:14]=3)=[CH:19][C:20]=2[CH2:26][CH2:25]1)=[O:44]
Reactant: CN(C)C(=O)Cl
Reactant: FC(F)COc1ccc(Cl)cc1-c1cccn2nc(Nc3ccc4c(c3)CCNCC4)nc12
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C(=O)N1CCc2ccc(Nc3nc4c(-c5cc(Cl)ccc5OCC(F)F)cccn4n3)cc2CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 50.4 %

Procedure:
To {8-[5-chloro-(2,2-difluoro-ethoxy)-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl}-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-amine (0.054 g, 0.110 mmol) in dichloromethane (4 mL) under an atmosphere of nitrogen was added triethylamine (0.0349 g, 0.345 mmol), N,N-dimethylcarbamoyl chloride (0.0159 mL, 0.172 mmol), followed by 4-dimethylaminopyridine (0.0014 g, 0.012 mmol) and was stirred at r.t. for 3 h and concentrated. The reaction was partitioned between dichloromethane/water, washed with brine, dried over sodium sulfate, and concentrated. The product was purified using Prep TLC plates (5% methanol in dichloromethane) and concentrated to give 7-{8-[5-chloro-2-(2,2-difluoro-ethoxy)-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino}-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acid dimethylamide (0.030 g, 48%). MP=98-99° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.58 (s, 1H), 8.78 (d, 1H), 7.80 (s, 1H), 7.65 (d, 1H), 7.48 (m, 3H), 7.30 (d, 1H), 7.05 (m, 2H), 6.25 (br m, 1H), 4.38 (m, 2H), 3.28 (m, 4H), 2.84 (m, 4H), 2.74 (s, 6H). MS=541 (MH)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:7](Br)[CH:8]=[CH2:9].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH2:9]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH:8]=[CH2:7]
Reactant: C1CCNCC1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCN1CCCCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The piperidine from Example 114 (56 mg, 0.15 mmol) was dissolved in dimethylformamide (2 mL) and was treated with allyl bromide (17 μL, 0.18 mmol), and potassium carbonate (63 mg, 0.45 mmol) and the mixture was stirred at r.t. for 4 hrs. The mixture was diluted with water (2 mL) and the solution washed with ethyl acetate (3×10 mL). The organic phase was dried (MgSO4) and evaporated to give a pale oil which was purified by column chromatography on silica gel eluting with 80% ethyl acetate in hexanes to give the N-allylpiperidine. 1H NMR (CDCl3) 7.42-7.37 (4H, m), 7.13-7.02 (2H, m), 6.90-6.83 (1H, m), 5.83-5.71 (1H, m), 5.12-5.08 (2H, m), 2.99-2.95 (2H, m), 2.86 (2H, d, J=6.5 Hz), 2.84-2.38 (4H, m), and 1.91-1.85 (2H, m); MS MH+=412(414).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([OH:15])=O.[NH:16]1[CH2:20][CH2:19][CH2:18][CH:17]1[CH2:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[C:13]([N:16]1[CH2:20][CH2:19][CH2:18][CH:17]1[CH2:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)=[O:15]
Reactant: Cc1onc(-c2ccccc2)c1C(=O)O
Reactant: c1cncc(CC2CCCN2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1onc(-c2ccccc2)c1C(=O)N1CCCC1Cc1cccnc1
Temperature: 25 °C

Procedure:
5-Methyl-3-phenylisooxazole-4-carboxylic acid (40 mg, 0.197 mmol), 3-(pyrrolidin-2-ylmethyl)pyridine (50.5 mg, 0.215 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (86.2 mg, 0.268 mmol) and diisopropylethylamine (25.4 mg, 0.197 mmol) were mixed in dimethylformamide (1.0 mL) and stirred at room temperature. Solvent was evaporated in vacuo, and the residue was taken up in methanol (1 mL), filtered and purified by preparative chromatography. The combined fractions were partitioned between NaHCO3 (sat) and ethylacetate. The organic layer was washed with water and concentrated in vacuo to afford the title compound. HRMS (ESI, pos. ion) m/z calcd for C21H21N3O2: 349.1426, found 349.1693.
Reaction SMILES: [NH:1]([C:8]1[CH:16]=[C:15]([C:17](O)=[O:18])[C:14]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:13][C:9]=1[C:10](O)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO>O>[CH:24]1[CH:25]=[C:26]2[C:17]([C:15]3[C:14]([NH:20][C:21]2=[CH:22][CH:23]=1)=[CH:13][C:9]1[C:10]([C:7]2[C:2]([NH:1][C:8]=1[CH:16]=3)=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:11])=[O:18]
Reactant: O=C(O)c1cc(Nc2ccccc2)c(C(=O)O)cc1Nc1ccccc1
Solvent: CO
Solvent: O
Product: O=c1c2ccccc2[nH]c2cc3c(=O)c4ccccc4[nH]c3cc12
Temperature: 133 °C

Procedure:
2,5-dianilino-terephthalic acid (one part) was dissolved in polyphosphoric acid (6.14 parts at 118.5%). The solution, already at 105° C., was heated to 133° C. for 3 hours then cooled to 100° C. and diluted to a fluid mass with water (0.5 parts). The solution was then drowned into methanol (11.6 parts) and the mixture heated at 125° C. for one hour to obtain a bluish red beta-phase quinacridone pigment.
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[CH:9][O:10][C:6]=2[CH:5]=[C:4]2[NH:11][C:12](=[O:22])[N:13]([C:14]3[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=3[F:21])[C:3]=12.C(N(CC)CC)C.[CH:30]1([S:33](Cl)(=[O:35])=[O:34])[CH2:32][CH2:31]1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH:30]1([S:33]([N:11]2[C:4]3=[CH:5][C:6]4[O:10][CH:9]=[N:8][C:7]=4[C:2]([F:1])=[C:3]3[N:13]([C:14]3[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=3[F:21])[C:12]2=[O:22])(=[O:35])=[O:34])[CH2:32][CH2:31]1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: O=c1[nH]c2cc3ocnc3c(F)c2n1-c1ccc(I)cc1F
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=c1n(-c2ccc(I)cc2F)c2c(F)c3ncoc3cc2n1S(=O)(=O)C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 110.5 %

Procedure:
To a solution of 4-fluoro-5-(2-fluoro-4-iodophenyl)-5H-imidazo[4′,5′:4,5]benzo[1,2-d]oxazol-6(7H)-one (30 mg, 0.07 mmol) in CH2Cl2 (3 mL) was added triethylamine (22 mg, 0.22 mmol) at 0° C. followed by cyclopropanesulfonyl chloride (16 mg, 0.11 mmol) and DMAP (5 mg). The mixture was stirred at room temperature for 1 h and washed with saturated NaHCO3 (aq.). The aqueous layer was extracted with CH2Cl2 (10 mL×2). The combined organic phase was washed with water (10 mL) and brine (10 mL) successively, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate, 5:1, v/v) to give the corresponding product (40 mg, 100% yield). 1H NMR (400 MHz, CDCl3): δ 8.09 (s, 1H), 7.99 (s, 1H), 7.39-7.11 (d, 2H), 7.05, (m, 1H), 3.40 (m, 1H), 1.71 (m, 2H), 0.91-0.85 (m, 2H).
Reaction SMILES: [Cl-].[NH4+].[CH3:3][C:4]1[CH:5]=[C:6]([C:13]2[CH:14]=[N:15][N:16]([CH2:18][C:19]([CH3:21])=[CH2:20])[CH:17]=2)[CH:7]=[C:8]([N+:10]([O-])=O)[CH:9]=1>C(O)C.O.[Fe]>[CH3:3][C:4]1[CH:9]=[C:8]([CH:7]=[C:6]([C:13]2[CH:14]=[N:15][N:16]([CH2:18][C:19]([CH3:21])=[CH2:20])[CH:17]=2)[CH:5]=1)[NH2:10]
Reactant: C=C(C)Cn1cc(-c2cc(C)cc([N+](=O)[O-])c2)cn1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: C=C(C)Cn1cc(-c2cc(C)cc(N)c2)cn1
Temperature: 70 °C

Procedure:
Iron (1.57 g, 28.2 mmol) and saturated aqueous ammonium chloride (11 mL) were added to a solution of 4-(3-methyl-5-nitrophenyl)-1-(2-methylallyl)-1H-pyrazole (2.42 g, 9.41 mmol) in ethanol (7 mL) and water (11 mL). The mixture was heated at 70° C. for 18 h, then allowed to cool to room temperature, passed through CELITE, washed with methanol, and concentrated under reduced pressure. The residue was diluted with EtOAc and washed with water, saturated aqueous sodium bicarbonate and brine. The organic layers were separated, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give 3-methyl-5-(1-(2-methylallyl)-1H-pyrazol-4-yl)aniline. MS ESI calc'd. for C14H18N3 [M+H]+ 228. found 228. 1H NMR (500 MHz, DMSO-d6) δ 7.92 (s, 1H), 7.68 (s, 1H), 6.52 (s, 2H), 6.21 (s, 1H), 4.92 (s, 2H), 4.87 (s, 1H), 4.70 (s, 1H), 4.66 (s, 2H), 2.14 (s, 3H). 1.60 (s, 3H).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([OH:14])=[C:10](Br)[CH:11]=2)[CH2:6][CH2:5]1)(=O)C.[CH2:15]([N:17]1[CH2:22][CH:21]=[C:20]([CH2:23]O)[CH2:19][CH2:18]1)[CH3:16]>>[CH2:15]([N:17]1[CH2:22][CH2:21][C:20]2([C:10]3[C:9](=[CH:8][C:7]4[CH2:6][CH2:5][NH:4][C:12]=4[CH:11]=3)[O:14][CH2:23]2)[CH2:19][CH2:18]1)[CH3:16]
Reactant: CCN1CC=C(CO)CC1
Reactant: CC(=O)N1CCc2cc(O)c(Br)cc21
Product: CCN1CCC2(CC1)COc1cc3c(cc12)NCC3
Yield: 45 %

Procedure:
This was prepared from 1-acetyl-6-bromo-2,3-dihydro-1H-indol-5-ol (Tetrahedron, 1973, 29 (8), 1115) and 1-ethyl-1,2,3,6-tetrahydropyridine-4-methanol (D108), following the procedure of Description 8 (alternative preparation), steps a), b), and c). This gave the title compound (overall yield: 45%) as a fine grey powder.
Reaction SMILES: [CH2:1]([CH:3]([NH:8][NH2:9])[C:4]([CH3:7])([CH3:6])[CH3:5])[CH3:2].FC1C([O:17][C:18]([C:20]2[CH:38]=[CH:37][C:23]3[O:24][CH2:25][C@@H:26]([C:28](C)(C)[O:29][SiH2]C(C)(C)C)[O:27][C:22]=3[C:21]=2[CH3:39])=O)=C(F)C(F)=C(F)C=1F>C(OCC)(=O)C>[CH2:1]([CH:3]([NH:8][NH:9][C:18]([C:20]1[CH:38]=[CH:37][C:23]2[O:24][CH2:25][C@H:26]([CH2:28][OH:29])[O:27][C:22]=2[C:21]=1[CH3:39])=[O:17])[C:4]([CH3:7])([CH3:6])[CH3:5])[CH3:2]
Reactant: Cc1c(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)ccc2c1O[C@H](C(C)(C)O[SiH2]C(C)(C)C)CO2
Reactant: CCC(NN)C(C)(C)C
Solvent: CCOC(C)=O
Product: CCC(NNC(=O)c1ccc2c(c1C)O[C@@H](CO)CO2)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To the biphasic preparation of (1-ethyl-2,2-dimethyl-propyl)-hydrazine described above, was added a solution of approximately one gram 3(S)-(tert-butyl-dimethyl-silanyloxymethyl)-5-methyl-2,3-dihydro-benzo[1,4]dioxine-6-carboxylic acid pentafluorophenyl ester dissolved in 10 mL ethyl acetate. The mixture was stirred at room temperature for 2 hours, after which time the aqueous phase was withdrawn and replaced with 1 M K2CO3. The mixture was stirred overnight. The aqueous layer was separated off, and the organic layer was extracted once with 1 M K2CO3 and then once with water. The organic phase was dried. The crude product was chromatographed on silica gel using a step gradient of 10% ether in hexane followed by neat ether, yielding 3(S)-hydroxymethyl-5-methyl-2,3-dihydro-benzo[1,4]dioxine-6-carboxylic acid N′-(1-ethyl-2,2-dimethyl-propyl)-hydrazide. 1H NMR (500 MHz, CDCl3) δ (ppm): 7.15 (br, 1H), 6.85 (d, 1H), 6.73 (d, 1H), 4.85 (br, 1H), 4.3 (d, 1H), 4.25 (m, 1H), 4.1 (dd, 1H), 3.87 (m, 2H), 2.41 (m, 1H), 2.29 (s, 3H), 1.8 (br, 1H); 1.65 (m, 1H), 1.3 (m, 1H), 1.45 (t, 3H), 0.98 (s, 9H); TLC: Rf.=0.23 (1:1 ethyl acetate:hexane).
Reaction SMILES: N1C=CC=CC=1.[Cl:7][C:8]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:9]=1[O:10][CH2:11][C:12](Cl)=[O:13].[NH2:20][C:21]1[N:25]([C:26]2[C:31]([Cl:32])=[CH:30][C:29]([C:33]([F:36])([F:35])[F:34])=[CH:28][C:27]=2[Cl:37])[N:24]=[CH:23][CH:22]=1>ClCCl>[Cl:7][C:8]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:9]=1[O:10][CH2:11][C:12]([NH:20][C:21]1[N:25]([C:26]2[C:31]([Cl:32])=[CH:30][C:29]([C:33]([F:34])([F:36])[F:35])=[CH:28][C:27]=2[Cl:37])[N:24]=[CH:23][CH:22]=1)=[O:13]
Reactant: Nc1ccnn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: O=C(Cl)COc1ccc(Cl)cc1Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(COc1ccc(Cl)cc1Cl)Nc1ccnn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.3 %

Procedure:
2.2 ml (0.0275 mol) of anhydrous pyridine and 6.7 g (0.027 mol) of 96.3 percent strength 2,4-dichlorophenoxyacetyl chloride are added successively to 8 g (0.027 mol) of 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-pyrazole (cf. U.S. Pat. No. 4,614,533, supra, in 60 ml of dichloromethane with stirring at 0° C. to 5° C. and the mixture is stirred for 16 hours at room temperature. The mixture is worked up by adding 100 ml of dichloromethane, washing successively with dilute hydrochloric acid, saturated sodium bicarbonate solution and saturated sodium chloride solution, drying the organic phase over magnesium sulphate and removing the solvent in vacuo. 12.7 g (94.3% of theory) of 5-(2,4-dichlorophenoxyacetamido)-1-(2,6-dichloro-4-trifluoromethylphenyl)-pyrazole of melting point 167° C.-180° C. are obtained.
Reaction SMILES: [CH2:1]([N:3](C(C)C)[CH:4](C)C)C.[C:10]([C:13]1[CH:14]=[C:15]([C:30]([OH:32])=O)[CH:16]=[C:17]2[C:22]=1[O:21][C:20]([N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)=[CH:19][C:18]2=[O:29])(=[O:12])[CH3:11].Cl.CNC>C(Cl)Cl>[C:10]([C:13]1[CH:14]=[C:15]([C:30]([N:3]([CH3:4])[CH3:1])=[O:32])[CH:16]=[C:17]2[C:22]=1[O:21][C:20]([N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)=[CH:19][C:18]2=[O:29])(=[O:12])[CH3:11]
Reactant: CC(=O)c1cc(C(=O)O)cc2c(=O)cc(N3CCOCC3)oc12
Reactant: CCN(C(C)C)C(C)C
Agent: CNC
Agent: Cl
Solvent: ClCCl
Product: CC(=O)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Yield: 44.4 %

Procedure:
N-ethyl-N-isopropylpropan-2-amine (9.4 mL, 53.9 mmol) was added to 8-acetyl-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (5.7 g, 18 mmol) in DCM (100 mL). Five minutes later dimethylamine hydrochloride (2.9 g, 35.9 mmol) and 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium tetrafluoroborate (6.92 g, 21.6 mmol) were added. The mixture was diluted with DCM, washed with NaHCO3, dried over magnesium sulfate and concentrated to afford the crude product which was purified by flash chromatography on silica gel eluting with 0 to 5% MeOH/DCM. The solvent was evaporated to dryness to afford 8-acetyl-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (2.75 g, 46%) as a yellow solid. Mass Spectrum: M+H+ 345.
Reaction SMILES: [CH2:1]([CH:3]([CH2:20][CH3:21])[CH:4]([C:6]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[N:9]=[CH:8][CH:7]=1)O)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(P([N:67]=[N+:68]=[N-:69])(C2C=CC=CC=2)=O)C=CC=CC=1>C1COCC1>[N:67]([CH:4]([C:6]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[N:9]=[CH:8][CH:7]=1)[CH:3]([CH2:20][CH3:21])[CH2:1][CH3:2])=[N+:68]=[N-:69]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CCC(CC)C(O)c1ccnn1Cc1ccc(OC)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCC(CC)C(N=[N+]=[N-])c1ccnn1Cc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 15.5 h
Yield: 65.5 %

Procedure:
To 2-ethyl-1-[1-(4-methoxybenzyl)-1H-pyrazol-5-yl]butan-1-ol (1.21 g, 4.20 mmol) in THF (40 mL) at 0° C. was added triphenylphosphine (1.65 g, 6.29 mmol), diethyl azodicarboxylate (1.0 mL, 6.3 mmol), and diphenylphosphoryl azide (1.4 mL, 6.3 mmol). The reaction mixture was warmed to room temperature and stirred for 15.5 h. The solvent was removed in vacuo and the resulting residue was purified by column chromatography (EtOAc/hexanes, 1:9, then 1:4) to give 0.862 g (66%) of 5-(1-azido-2-ethylbutyl)-1-(4-methoxybenzyl)-1H-pyrazole.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:9]=[C:8]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][CH:11]=2)[CH:7]=[CH:6][N:5]=1.I[CH3:20]>CN(C=O)C>[Cl:3][C:4]1[N:9]=[C:8]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([CH3:20])[CH:11]=2)[CH:7]=[CH:6][N:5]=1
Reactant: CI
Reactant: Clc1nccc(-c2c[nH]c3ccccc23)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cc(-c2ccnc(Cl)n2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 110.8 %

Procedure:
NaH (60% dispersion in mineral oil, 0.16 g, 7 mmol) was added at 0° C. to 3-(2-chloro-pyrimidin-4-yl)-1H-indole (0.24 g, 1 mmol) in DMF (8 mL). The resulting mixture was stirred for 10 min, then iodomethane (0.20 mL, 3.2 mmol) was added, and the reaction mixture was warmed to RT and poured onto ice water. The resulting mixture was extracted with EtOAc, the combined organics washed twice with water, dried over Na2SO4, filtered and concentrated under reduced pressure to give 3-(2-chloro-pyrimidin-4-yl)-1-methyl-1H-indole (270 mg) as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[CH:3]([CH3:8])[CH2:4][C:5](O)=[O:6].CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.Cl.[F:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH:37]1[O:41][N:40]=[C:39]([C:42]2[N:43]=[C:44]([CH:47]3[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]3)[S:45][CH:46]=2)[CH2:38]1.C(N(CC)CC)C>ClCCl.CN(C)C1C=CN=CC=1>[F:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH:37]1[O:41][N:40]=[C:39]([C:42]2[N:43]=[C:44]([CH:47]3[CH2:52][CH2:51][N:50]([C:5](=[O:6])[CH2:4][CH:3]([CH3:8])[C:2]([F:10])([F:9])[F:1])[CH2:49][CH2:48]3)[S:45][CH:46]=2)[CH2:38]1
Reactant: CC(CC(=O)O)C(F)(F)F
Reactant: Fc1ccccc1C1CC(c2csc(C3CCNCC3)n2)=NO1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(CC(=O)N1CCC(c2nc(C3=NOC(c4ccccc4F)C3)cs2)CC1)C(F)(F)F
Reaction time: 0.08 h

Procedure:
To a solution of 4,4,4-trifluoro-3-methyl-butanoic acid (64 mg, 0.408 mmol) in dichloromethane (3 mL) was added 1-propanephosphonic acid cyclic anhydride solution (50% in ethyl acetate, 0.5 mL). After stirring for 5 minutes, 4-[4-[5-(2-fluorophenyl)-4,5-dihydro-3-isoxazolyl)-2-thiazolyl]piperidine hydrochloride (i.e. the product of Step C) (150 mg, 0.408 mmol), triethylamine (0.1 mL) and 4-dimethylaminopyridine (5 mg) were sequentially added The reaction mixture was stirred for 3 h, and then concentrated under reduced pressure. The resulting material was purified by column chromatography on silica gel to provide the title compound, a compound of the present invention, as an oil (151 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:6][C:5]=1[NH:15][C:16](=[O:23])[O:17][CH2:18][CH:19]1[CH2:22][NH:21][CH2:20]1)([O-:3])=[O:2].[CH2:24](Cl)Cl.C=O.C([BH3-])#N.[Na+]>CC#N>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:6][C:5]=1[NH:15][C:16](=[O:23])[O:17][CH2:18][CH:19]1[CH2:20][N:21]([CH3:24])[CH2:22]1)([O-:3])=[O:2]
Reactant: ClCCl
Reactant: O=C(Nc1cc(-c2cccs2)ccc1[N+](=O)[O-])OCC1CNC1
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC#N
Product: CN1CC(COC(=O)Nc2cc(-c3cccs3)ccc2[N+](=O)[O-])C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
To a stirred solution of azetidin-3-ylmethyl (2-nitro-5-(thiophen-2-yl)phenyl)carbamate (0.09 g, 0.26 mmol, 1.0 eq.) in CH3CN:CH2Cl2 was added aq. formaldehyde (0.77 mmol, 3.0 eq.). The reaction mixture was stirred at room temperature for 30 min then cooled to 0° C. Sodium cyanoborohydride (0.03 g, 0.46 mmol, 1.8 eq.) was added slowly. The reaction was quenched with an aqueous saturated solution of sodium bicarbonate. The product was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, 5% MeOH/CH2Cl2) to obtain (1-methylazetidin-3-yl)methyl (2-nitro-5-(thiophen-2-yl)phenyl)carbamate (0.07 g, 75% yield).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@:10]21[C:47]1[C:42](=[CH:43][C:44]([Cl:57])=[C:45]([CH2:48][C:49]3[CH:54]=[CH:53][C:52]([CH2:55][CH3:56])=[CH:51][CH:50]=3)[CH:46]=1)[CH:41](O)[CH2:40]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(S(F)(F)[F:65])CC>ClCCl>[CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@:10]21[C:47]1[C:42](=[CH:43][C:44]([Cl:57])=[C:45]([CH2:48][C:49]3[CH:54]=[CH:53][C:52]([CH2:55][CH3:56])=[CH:51][CH:50]=3)[CH:46]=1)[CH:41]([F:65])[CH2:40]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: CCc1ccc(Cc2cc3c(cc2Cl)C(O)C[C@]32O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1
Solvent: ClCCl
Product: CCc1ccc(Cc2cc3c(cc2Cl)C(F)C[C@]32O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 87.8 %

Procedure:
To a −78° C. solution of (1S,3′R,4′S,5′R,6′R)-3′,4′,5′-tris(benzyloxy)-6′-(benzyloxymethyl)-5-chloro-6-(4-ethylbenzyl)-2,3,3′,4′,5′,6′-hexahydrospiro[indene-1,2′-pyran]-3-ol (40 mg, 0.05 mmol) in dry dichloromethane (2.0 mL) was added dropwise a solution of DAST reagent (0.014 mL, 0.1 mmol, 95%) in 0.5 mL of dry dichloromethane. The reaction mixture was stirred for 2 h at −78° C. and quenched by addition of 1 mL of saturated aqueous NaHCO3 solution when TLC showed the reaction was complete. The organic layer was separated and the aqueous layer was extracted 2× with CH2Cl2 (10 mL). The combined organic layers were washed 2× with NaHCO3 (10 mL), 3× with brine (10 mL) prior to drying over anhydrous Na2SO4. Concentrated under reduced pressure and purification of the crude product by prepared TLC provided 35 mg of the pure product.