Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][P:2]([CH:24]([NH:32][C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([O:4][C@@H:5]([CH3:23])[C:6]([N:8]1[CH2:22][CH2:21][CH2:20][C@H:9]1[C:10]([O:12]CC1C=CC=CC=1)=[O:11])=[O:7])=[O:3].C(O)C>O1CCOCC1.[OH-].[Li+].O>[OH:3][P:2]([CH:24]([NH:32][C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34])[CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)([O:4][C@@H:5]([CH3:23])[C:6]([N:8]1[CH2:22][CH2:21][CH2:20][C@H:9]1[C:10]([OH:12])=[O:11])=[O:7])=[O:1]
Reactant: C[C@H](OP(=O)(O)C(Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCO
Solvent: O
Product: C[C@H](OP(=O)(O)C(Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The phenylmethyl ester product from part (a) (4.12 g., 6.9 mmole) is dissolved in dioxane (15 ml.) and 1N lithium hydroxide (15 ml.). Ethanol (several ml.) is added to solubilize the salts, and the reaction mixture is stirred overnight at room temperature under argon. The reaction mixture is diluted with water and washed with ether and ethyl acetate. This aqueous solution is acidified and extracted with ethyl acetate. This ethyl acetate solution is washed with brine, dried over sodium sulfate, and concentrated to give 1-[(S)-2-[[hydroxy[2-phenyl-1-[[(phenylmethoxy)carbonyl]amino]ethyl]phosphinyl]oxy]-1-oxopropyl]-L-proline as a viscous white oil.
Reaction SMILES: C(N(CC)CC)C.[N:8]1([C:14]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:15]=2[C:16]([NH2:25])=[N:17][C:18]([NH2:24])=[N:19]3)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[F:26][C:27]1[C:34]([CH3:35])=[CH:33][CH:32]=[CH:31][C:28]=1[CH2:29]Br>CN(C)C=O>[F:26][C:27]1[C:34]([CH3:35])=[CH:33][CH:32]=[CH:31][C:28]=1[CH2:29][N:11]1[CH2:12][CH2:13][N:8]([C:14]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:15]=2[C:16]([NH2:25])=[N:17][C:18]([NH2:24])=[N:19]3)[CH2:9][CH2:10]1
Reactant: Nc1nc(N)c2c(N3CCNCC3)cccc2n1
Reactant: Cc1cccc(CBr)c1F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cccc(CN2CCN(c3cccc4nc(N)nc(N)c34)CC2)c1F
Temperature: 60 °C
Yield: 50.5 %

Procedure:
In an 8 mL vial with stir bar, triethylamine (40 mg; 0.4 mmol) was added to a mixture of 5-piperazin-1-yl-quinazoline-2,4-diamine (50 mg; 0.2 mmol) and 2-fluoro-3-methylbenzyl bromide (54 mg; 0.27 mmol) in dimethylformamide and heated to 60° C. for 16 hours. Mixture was quenched with 1 mL of 1N NaOH and after 1.5 hours solids were collected by filtration and triturated with ethanol to obtain 37 mg of title compound. (51% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.86 (s, 1H), 7.2 (m, 3H), 7.07 (t, J=7.6 Hz, 1H), 6.95 (dd, J=8.4, 0.8 Hz, 1H), 6.84 (dd, J=7.6, 0.8 Hz, 1H), 5.90 (br s, 2H), 3.59 (s, 2H), 2.98 (d, J=11.2 Hz, 2H), 2.89 (d, J=12.0 Hz, 2H), 2.81 (t, J=9.6 Hz, 2H), 2.313 (t, J=9.2 Hz, 2H), 2.24 (s, 3H). ESIMS+367.6 m/z
Reaction SMILES: [Cl:1][C:2]1[C:24]([Cl:25])=[CH:23][C:5]2[N:6]([CH2:20][O:21][CH3:22])[C:7]([C:9]3[NH:10][C:11]4[C:16]([CH:17]=3)=[CH:15][C:14]([CH:18]=[O:19])=[CH:13][CH:12]=4)=[N:8][C:4]=2[CH:3]=1.IC.[CH3:28]C(C)([O-])C.[K+].O>CN(C)C=O>[Cl:1][C:2]1[C:24]([Cl:25])=[CH:23][C:5]2[N:6]([CH2:20][O:21][CH3:22])[C:7]([C:9]3[N:10]([CH3:28])[C:11]4[C:16]([CH:17]=3)=[CH:15][C:14]([CH:18]=[O:19])=[CH:13][CH:12]=4)=[N:8][C:4]=2[CH:3]=1
Reactant: CC(C)(C)[O-]
Reactant: COCn1c(-c2cc3cc(C=O)ccc3[nH]2)nc2cc(Cl)c(Cl)cc21
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COCn1c(-c2cc3cc(C=O)ccc3n2C)nc2cc(Cl)c(Cl)cc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.8 %

Procedure:
To a solution of 5,6-dichloro-2-[5-formylindol-2-yl]-1-(methoxymethyl)benzimidazole obtained in Example 47 (32 mg, 0.086 mmol) in dimethylformamide (2 mL) were added iodomethane (0.027 mL, 0.43 mmol) and potassium tert-butoxide (19 mg, 0.17 mmol) under nitrogen atmosphere, and the mixture was stirred at room temperature for 18 h. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure to afford 5,6-dichloro-2-[5-formyl-1-methylindol-2-yl]-1-methoxymethylbenzimidazole (30 mg, 90%).
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][C:7]2[NH:8][C:9](=[O:22])[C:10](=[CH:12][C:13]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[NH:15][CH:14]=3)[S:11][C:6]=2[CH:5]=1)([O-])=O.O.NN>[Ni].C(O)C>[NH2:1][C:4]1[CH:24]=[CH:23][C:7]2[NH:8][C:9](=[O:22])[C:10](=[CH:12][C:13]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[NH:15][CH:14]=3)[S:11][C:6]=2[CH:5]=1
Reactant: O=C1Nc2ccc([N+](=O)[O-])cc2SC1=Cc1c[nH]c2ccccc12
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: O
Product: Nc1ccc2c(c1)SC(=Cc1c[nH]c3ccccc13)C(=O)N2
Yield: 47.7 %

Procedure:
A catalytic amount of Raney nickel was added portionwise with stirring to a mixture of 7-nitro-2-[(indol-3-yl)methylene]-2H-1,4-benzothiazin-3(4H)-one (see Example 31) (0.39 g, 1.16 mmol) and hydrazine hydrate (98%) (0.60 ml) in ethanol (15 ml). The reaction mixture was refluxed for 5 h, then filtered hot. The solid residue was boiled with ethanol (100 ml) and filtered hot. The combined filtrates were brought to dryness in vacuo and chromatographed on silica gel using a gradient of (9:1) to (8:2) dichloromethane:ethanol as the mobile phase to afford 0.17 g (35%) product.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:10][N+:11]([O-])=O>CO.[Ni]>[NH2:11][CH2:10][CH:9]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:18])[CH3:20])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=1[Cl:1]
Reactant: CC(C)(C)OC(=O)NC(C[N+](=O)[O-])c1cccc(Cl)c1Cl
Agent: [Ni]
Solvent: CO
Product: CC(C)(C)OC(=O)NC(CN)c1cccc(Cl)c1Cl

Procedure:
A solution of 440 mg (1.31 mmol) of the compound of Example 23A in 100 ml of methanol was hydrogenated in a continuous-flow hydrogenation apparatus fitted with a Raney-nickel cartridge (H-Cube from Thales Nano, Budapest, Model HC-2-SS) at a flow rate of 1 ml/min, a temperature of 40° C. and at standard pressure. After the reaction had ended, the solution was freed from the methanol on a rotary evaporator and the residue was dried briefly under high vacuum. This gave 370 mg (91% of theory) of the title compound.
Reaction SMILES: [CH:1]1([C:4]2[O:5][CH:6]=[C:7]([C:9]3([NH2:12])[CH2:11][CH2:10]3)[N:8]=2)[CH2:3][CH2:2]1.CC1ON=C(C2(N)CC2)C=1.CC1C=CC(C2(N)CC2)=NC=1.C(OC(=O)NCC1C=NC(C2(N)CC2)=CC=1)(C)(C)C.CN(CC1C=CC(C2(N)CC2)=NC=1)C.[Si](OCC1C=CC(C2(N)CC2)=NC=1)(C(C)(C)C)(C)C.C([SiH2]OC(C)(C)C1C=CN=C(C2(N)CC2)C=1)(C)(C)C.BrC1C=CC(C2(N)CC2)=NC=1.IC1C=CN=C(C2(N)CC2)C=1.NC1(C2N=CC(N(C)C)=CC=2)CC1.CC1SC=C(C2(N)CC2)N=1>>[CH:1]([C:4]1[O:5][CH:6]=[C:7]([C:9]2([NH2:12])[CH2:10][CH2:11]2)[N:8]=1)([CH3:3])[CH3:2]
Reactant: NC1(c2coc(C3CC3)n2)CC1
Agent: CC(C)(C)OC(=O)NCc1ccc(C2(N)CC2)nc1
Agent: CC(C)(C)[SiH2]OC(C)(C)c1ccnc(C2(N)CC2)c1
Agent: CC(C)(C)[Si](C)(C)OCc1ccc(C2(N)CC2)nc1
Product: CC(C)c1nc(C2(N)CC2)co1

Procedure:
1-(2-Cyclopropyloxazol-4-yl)cyclopropylamine; 1-(5-Methylisoxazol-3-yl)cyclopropylamine; 1-(5-Methylpyridin-2-yl)cyclopropylamine; [6-(1-Aminocyclopropyl)pyridin-3-ylmethyl]carbamic acid tert-butyl ester; 1-(5-Dimethylaminomethylpyridin-2-yl)cyclopropylamine; 1-[5-(tert-Butyldimethylsilanyloxymethyl)pyridin-2-yl]cyclopropylamine (Carbonitrile precursor was synthesized according to literature procedure: LecClerc et al. J. Het. Chem. 1993, 30, 631.); 1-[4-(tert-Butyl-dimethyl-silanyloxymethyl)-pyridin-2-yl]-cyclopropylamine (Carbonitrile precursor was synthesized according to literature procedure: LecClerc et al. J. Het. Chem. 1993, 30, 631.); 1-(5-Bromo-pyridin-2-yl)-cyclopropylamine; 1-(4-Iodo-pyridin-2-yl)-cyclopropylamine; [6-(1-Amino-cyclopropyl)-pyridin-3-yl]-dimethyl-amine; 1-(2-methyl-thiazol-4-yl)-cyclopropylamine:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=3)[NH:9]2)=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[C:33](Cl)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>ClCCl>[C:33]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:17]([CH3:18])([CH3:19])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=3)[NH:9]2)=[CH:6][CH:7]=1)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(N)cc1)N2
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(NC(=O)c3ccccc3)cc1)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.8 %

Procedure:
To a solution of methyl 2-(4-aminophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxy late (100 mg, 0.32 mmol) and N,N-diisopropylethylamine (0.11 mL, 0.64 mmol) in dichloro methane (5 mL) was added benzoyl chloride (0.04 mL, 0.35 mmol) with ice cooling. Upon completion of addition, the resultant solution was allowed to warm back to room temperature and stir overnight. LC-MS showed the reaction was complete. Solvent was removed in vacuo and the residue was purified by preparative Thin layer chromatography to afford 70 mg of methyl 2-(4-benzamidophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate as a white solid. Yield: 53%. MS (ESI+APCI) M+1=415.20.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH3:24])[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3Cl)[C:3]=12.[CH3:25]N1C(N)=CC(C2C=CC=CC=2)=N1.C1(C)C=CC(C#C)=CC=1>>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([CH3:25])=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH3:24])[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12
Reactant: Cn1nc(-c2ccccc2Cl)c2c(Cl)c(-c3ccccc3)nnc21
Reactant: Cn1nc(-c2ccccc2)cc1N
Agent: C#Cc1ccc(C)cc1
Product: Cc1ccc(-c2nnc3c(c(-c4ccccc4)nn3C)c2Cl)cc1

Procedure:
Compound 11 was synthesised following similar procedures outlined in Example 1 (Compound 37), starting from Step 2 using 1-methyl-3-phenyl-1H-pyrazol-5-amine instead of 3-(2-chlorophenyl)-1-methyl-1H-pyrazol-5-amine and 4-tolylacetylene instead of phenyl acetylene in Step 4.
Reaction SMILES: C([O:3][C:4](=[O:24])[C:5]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=1)([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)C.[CH3:25][C:26]1[O:30][C:29]([C:31]2[S:32][CH:33]=[CH:34][CH:35]=2)=[N:28][C:27]=1[CH2:36][CH2:37]OS(C1C=CC(C)=CC=1)(=O)=O>>[CH3:23][O:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[O:15][C:5]([CH3:14])([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:37][CH2:36][C:27]2[N:28]=[C:29]([C:31]3[S:32][CH:33]=[CH:34][CH:35]=3)[O:30][C:26]=2[CH3:25])=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:24]
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3cccs3)oc2C)cc1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1cccc(OC)c1
Product: COc1cccc(OC(C)(Cc2ccc(OCCc3nc(-c4cccs4)oc3C)cc2)C(=O)O)c1

Procedure:
The title compound was prepared from 3-(4-hydroxy-phenyl)-2-(3-methoxy-phenoxy)-2-methyl-propionic acid ethyl ester and toluene-4-sulfonic acid 2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethyl ester using the procedure of Example 74. 1H NMR (400 MHz, CDCl3) δ 7.58 (d, 1H, J=3.52 Hz), 7.36 (d, 1H, J=5.08 Hz), 7.17-7.13 (m, 3H), 7.08-6.99 (m, 1H), 6.82 (d, 2H, J=8.60 Hz), 6.62-6.59 (m, 1H), 6.52-6.46 (m, 2H), 4.19 (t, 2H, J=6.65 Hz), 3.75 (s, 3H), 3.24 (d, 1H, J=14.08 Hz), 3.16 (d, 1H, J=14.08 Hz), 2.95 (t, 2H, J=6.65 Hz), 2.35 (s, 3H), 1.45 (s, 3H); HRMS (ES+) m/z exact mass calcd for C27H28NO6S 494.1637, found 494.1642.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:18])[CH2:12][C:11]2[NH:10][N:9]=[C:8]([C:13]([F:16])([F:15])[F:14])[C:7]=2[C:6](=[O:17])[CH2:5]1.[Br:19][C:20]1[CH:27]=[C:26](F)[CH:25]=[CH:24][C:21]=1[C:22]#[N:23]>CS(C)=O>[Br:19][C:20]1[CH:27]=[C:26]([N:10]2[C:11]3[CH2:12][C:4]([CH3:18])([CH3:3])[CH2:5][C:6](=[O:17])[C:7]=3[C:8]([C:13]([F:16])([F:15])[F:14])=[N:9]2)[CH:25]=[CH:24][C:21]=1[C:22]#[N:23]
Reactant: CC1(C)CC(=O)c2c(C(F)(F)F)n[nH]c2C1
Reactant: N#Cc1ccc(F)cc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC1(C)CC(=O)c2c(C(F)(F)F)nn(-c3ccc(C#N)c(Br)c3)c2C1
Temperature: 45 °C
Yield: 63.2 %

Procedure:
Sodium hydride (168 mg, 7.02 mmol, 1.0 eq.) was added to a solution of 6,6-dimethyl-3-trifluoromethyl-1,5,6,7-tetrahydro-indazol-4-one (1.63 g, 7.02 mmol, 1.0 eq.) in 35 mL of anhydrous dimethyl sulfoxide. After 15 min 2-bromo-4-fluorobenzonitrile (2.25 g, 11.23 mmol, 1.6 eq.) was added as a solid. The reaction mixture was heated at 45° C. After 23 h the reaction mixture was cooled to ambient temperature and quenched with 10 mL of saturated aqueous ammonium chloride. The mixture was diluted with water and extracted with ethyl acetate (4×). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified on a Biotage (SiO2, hexanes-ethyl acetate) to afford 2-bromo-4-(6,6-dimethyl-4-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-indazol-1-yl)-benzonitrile (1.83 g, 63%) as an off-white powder, LC/MS: (M+H)=412.0.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([OH:18])=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]=O>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:1]([O:8][C:9]([N:11]1[C@@H:12]([CH:13]([CH3:15])[CH3:14])[C:16](=[O:18])[O:17][CH2:19]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=O
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)[C@H]1C(=O)OCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 90.1 %

Procedure:
In toluene (250 mL) were suspended benzyloxycarbonyl-L-valine (25.1 g), paraformaldehyde (6.70 g) and p-toluenesulfonic acid monohydrate (0.19 g), and the suspension was heated at reflux while removing water produced. At the end of the reaction, the mixture was cooled to room temperature, washed with saturated aqueous sodium hydrogen carbonate solution and saturated saline. The toluene solution was dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure to give the title compound (23.7 g) as colorless transparent syrup in an yield of 90%.
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=S.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:30](O)[CH2:31][CH2:32][CH:33]([C:35]2[CH:40]=[C:39]([O:41][CH3:42])[C:38]([O:43][CH3:44])=[C:37]([O:45][CH3:46])[CH:36]=2)[OH:34])[CH:20]=[C:21]([N+:27]([O-:29])=[O:28])[C:22]=1[O:23][CH2:24][CH2:25][CH3:26].O>N1C=CC=CC=1>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:30]2[CH2:31][CH2:32][CH:33]([C:35]3[CH:40]=[C:39]([O:41][CH3:42])[C:38]([O:43][CH3:44])=[C:37]([O:45][CH3:46])[CH:36]=3)[O:34]2)[CH:20]=[C:21]([N+:27]([O-:29])=[O:28])[C:22]=1[O:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCOc1c(OC)cc(C(O)CCC(O)c2cc(OC)c(OC)c(OC)c2)cc1[N+](=O)[O-]
Agent: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Solvent: O
Product: CCCOc1c(OC)cc(C2CCC(c3cc(OC)c(OC)c(OC)c3)O2)cc1[N+](=O)[O-]
Temperature: 120 °C
Reaction time: 1.5 h

Procedure:
A suspension of P4S10 (19.25 g, 43.3 mmol) in 250 mL of pyridine was heated at 120° C. for 75 minutes. To this suspension was then added a solution of 1-(3-methoxy-4-propoxy-5-nitrophenyl)-4-(3,4,5-trimethoxyphenyl)-butane-1,4-diol (4.65 g, 10 mmol) in 50 mL of pyridine. The temperature was reduced to 90° C. and stirring continued for an additional 90 minutes. After cooling, ice and water were added, the mixture was extracted with methylene chloride. The organic layer was washed with water, 5% HCl, water, sodium bicarbonate and saturated aqueous sodium chloride, and then dried over magnesium sulfate, filtered and evaporated.
Reaction SMILES: C[O:2][C:3]1[C:4](=[O:17])[NH:5][C:6]2[CH:14]=[C:13]([CH3:15])[C:12]([CH3:16])=[CH:11][C:7]=2[C:8](=[O:10])[CH:9]=1.B(Br)(Br)Br.C([O-])(O)=O.[Na+].Cl>C(Cl)Cl.CCO>[OH:2][C:3]1[C:4](=[O:17])[NH:5][C:6]2[CH:14]=[C:13]([CH3:15])[C:12]([CH3:16])=[CH:11][C:7]=2[C:8](=[O:10])[CH:9]=1
Reactant: COc1cc(=O)c2cc(C)c(C)cc2[nH]c1=O
Agent: BrB(Br)Br
Agent: Cl
Agent: O=C([O-])O
Solvent: CCO
Solvent: ClCCl
Product: Cc1cc2[nH]c(=O)c(O)cc(=O)c2cc1C
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a stirred suspension of 3-methoxy-7,8-dimethyl-1H-1-benzazepine-2,5-dione (270 mg, 1.17 mmol) in dry CH2CH2 (2.7 mL, distilled from CaH2) under N2, there was added a solution of BBr3 in CH2Cl2 (2.7 mL, 1M, Aldrich) in one portion over 20 seconds at rt. The reaction instantaneously became homogeneous and orange, then a brown precipitate formed after a few seconds. The reaction was allowed to stir under N2 at rt for 45 min. The reaction was added to saturated NaHCO3 (30 mL) and was allowed to stir for 15 min at rt to give a yellow suspension. The resulting suspension was acidified with concd HCl (pH 2), the acidic suspension stirred for 10 min at rt, the solid collected by filtration and washed to neutrality with water (6×4 mL). The damp filter cake was crystallized from 95% EtOH (dissolved in 550 mL, hot filtered, coned to 210 mL, allowed to cool to rt) to yield a fine yellow solid (195 mg, 77%, pure by TLC, 1H NMR and C,H,N analysis); mp 302°-304° C. (dec. EtOH) (lit 288° C. (dec) Birchall, G. R. et al. Can. J. Chem. 52:610-615 (1974)); 1H NMR (DMSO-d6) δ2.24 (d, 6H), 6.39 (s, 1H), 7.24 (s, 1H), 7.80 (s, 1H), 10.46 (s, 1H), 11.49 (s, 1H); Anal. Calcd for C12H11NO3 : C, 66.35; H, 5.10; N, 6.45. Found: C, 66.30; H, 4.88; N, 6.25.
Reaction SMILES: [N:1]([CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6]1)=[N+]=[N-]>CO.[Pd]>[NH2:1][CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CCCC(CN=[N+]=[N-])C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCCC(CN)C1
Reaction time: 9 h

Procedure:
tert-butyl 3-(azidomethyl)piperidine-1-carboxylate (5.38 g, 22.40 mmol) was dissolved in MeOH (50 ml), and then Pd/C (5% mol) was added, followed by stirring under H2 (gas) for 9 hours. After the completion of the reaction, the reaction mixture was filtered through celite, followed by filtration and concentration under reduced pressure, and then the next reaction was advanced without purification.
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][C:6]([C:8]([O:10][CH3:11])=[O:9])=[CH:5][CH:4]=1.[OH:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20](=[O:22])[CH3:21])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O.CO.Cl>[CH2:19]([C:16]1[CH:15]=[CH:14][C:13]([O:12][CH2:2][C:3]2[O:7][C:6]([C:8]([O:10][CH3:11])=[O:9])=[CH:5][CH:4]=2)=[CH:18][CH:17]=1)[C:20]([CH3:21])=[O:22]
Reactant: CC(=O)Cc1ccc(O)cc1
Reactant: COC(=O)c1ccc(CCl)o1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CO
Solvent: CC(C)=O
Product: COC(=O)c1ccc(COc2ccc(CC(C)=O)cc2)o1

Procedure:
Methyl 5-chloromethyl-2-furoate (4.5 g) was added to a mixture of 4-hydroxyphenyl propan-2-one, ethylene ketal (5 g) and potassium carbonate (3.56 g) in acetone (150 ml) containing a catalytic amount of potassium iodide. The reaction mixture was stirred and heated under reflux for 4 hr., cooled and filtered. The filtrate was evaporated to an oil which was purified by column chromatography on silica gel. Elution with chloroform gave a crystalline solid which was stirred at ambient temperature for 4 hr. in a mixture of methanol (50 ml) and 2N hydrochloric acid (50 ml). The methanol was evaporated and the aqueous residue was extracted into dichloromethane. The organic extract was dried (MgSO4) and evaporated to give methyl 5-[4-acetonyl- phenoxymethyl]furan-2-carboxylate as an oil.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[BH4-].[Na+]>C(O)C>[Cl:1][CH2:2][CH2:3][CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5]
Reactant: O=C(CCCl)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OC(CCCl)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Chloropropiophenone (25.2 g) was dissolved in abs. ethanol (200 ml), NaBH4 (2.2 g) was slowly added and the mixture stirred overnight at R.T. The mixture was filtered and the filtrate evaporated to dryness. H2O was added and the solution extracted with ether, the ether phase dried (MgSO4) and evaporated. The resulting oil purified on silioagel CH2Cl2 as eluent giving 3-chloro-1-phenyl-1-propanol (compound 14), identified by 1H NMR.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH2:9][CH3:10])=[C:4]([Cl:11])[N:3]=1.C(N(CC)CC)C.[CH2:19]([NH:23][CH2:24][CH3:25])[CH2:20][CH2:21][CH3:22]>C(#N)C.O.Cl>[CH2:19]([N:23]([C:6]1[C:5]([CH2:9][CH3:10])=[C:4]([Cl:11])[N:3]=[C:2]([CH3:1])[N:7]=1)[CH2:24][CH3:25])[CH2:20][CH2:21][CH3:22]
Reactant: CCc1c(Cl)nc(C)nc1Cl
Reactant: CCCCNCC
Agent: Cl
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCCN(CC)c1nc(C)nc(Cl)c1CC
Yield: 88.3 %

Procedure:
A mixture of 2-methyl-5-ethyl-4,6-dichloro-pyrimidine (1.009 g, 5.28 mmol) in 5 ml of acetonitrile was treated with triethylamine (0.571 g, 5.65 mmol) and N-butyl-ethyl-amine (0.540 g, 5.31 mmol) and heated at reflux overnight. The mixture was diluted with water and dilute hydrogen chloride, and extracted with ethyl acetate. The organic layer was neutralized with saturated potassium carbonate and washed with brine, dried and concentrated to give 1.193 g of yellow oil which was purified through silica gel column chromatography to give 1.157 g (86%) of title compound as a yellow oil. 1H NMR (CDCl3) δ 0.90 (t, 3H), 1.13 (t, 3H), 1.18 (t, 3H), 1.1–1.33 (m, 2H), 1.4–1.6 (m, 2h), 2.41 (s, 3H), 2.62 (q, 2H), 3.25–3.48 (m, 4H) ppm.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C@H:7]([C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:18]([C:21]4[CH:30]=[CH:29][C:28]5[C:23](=[CH:24][C:25]([O:32][CH2:33][CH2:34][OH:35])=[C:26]([F:31])[CH:27]=5)[N:22]=4)=[N:19][N:20]=3)[CH:17]=2)[C:8]([F:11])([F:10])[F:9])[CH2:3]1.[C:36](=O)([O:46]C1C=CC([N+]([O-])=O)=CC=1)[O:37][CH2:38][C:39]1[O:40][C:41](=[O:45])[O:42][C:43]=1[CH3:44]>CN(C=O)C>[F:10][C:8]([F:9])([F:11])[C@H:7]([N:4]1[CH2:5][CH2:6][C@H:2]([NH:1][C:36](=[O:46])[O:37][CH2:38][C:39]2[O:40][C:41](=[O:45])[O:42][C:43]=2[CH3:44])[CH2:3]1)[C:12]1[CH:13]=[CH:14][C:15]2[N:16]([C:18]([C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][C:25]([O:32][CH2:33][CH2:34][OH:35])=[C:26]([F:31])[CH:27]=4)[N:22]=3)=[N:19][N:20]=2)[CH:17]=1
Reactant: Cc1oc(=O)oc1COC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: N[C@H]1CCN([C@H](c2ccc3nnc(-c4ccc5cc(F)c(OCCO)cc5n4)n3c2)C(F)(F)F)C1
Solvent: CN(C)C=O
Product: Cc1oc(=O)oc1COC(=O)N[C@H]1CCN([C@H](c2ccc3nnc(-c4ccc5cc(F)c(OCCO)cc5n4)n3c2)C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.5 %

Procedure:
To a solution of 2-((2-(6-((R)-1-((S)-3-aminopyrrolidin-1-yl)-2,2,2-trifluoroethyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-6-fluoro quinolin-7-yl)oxy)ethanol (125 mg, 0.255 mmol) in DMF (1.5 mL) was added a solution of (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 4-nitrophenyl carbonate (prepared according to procedures described in J. Med. Chem. 1999, 42, 3994-4000, 71.2 mg, 0.255 mmol) in DMF (1 mL). The reaction mixture was stirred at ambient temperature for 30 minutes. The reaction was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with water and brine, dried and concentrated. The residue was purified by flash chromatography on silica gel (DCM:MeOH, 70:1 to 40:1) to give (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ((S)-1-((R)-2,2,2-trifluoro-1-(3-(6-fluoro-7-(2-hydroxyethoxy)quinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethyl)pyrrolidin-3-yl)carbamate (131 mg, 80%). LCMS APCI (+) m/z 647 (M+H).