Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9](=[O:11])C)[CH:6]=[CH:7][CH:8]=1.[BH4-].[Na+].Cl.[CH3:15]O>>[CH3:1][O:2][C:3]1[CH2:4][C:5]([CH3:15])([CH:6]=[CH:7][CH:8]=1)[CH2:9][OH:11]
Reactant: CO
Reactant: COc1cccc(C(C)=O)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Product: COC1=CC=CC(C)(CO)C1
Temperature: 0 °C
Yield: 94 %

Procedure:
To m-methoxyacetophenone (100 g, 0.665 mol) in 400 mL of methanol was added with cooling sodium borohydride (30.22 g, 0.799 mol) over a period of 1 h and the mixture was stirred, poured into ice-water, and neutralized with conc. HCl. The above mixture was extracted with ether (3×400 mL), the organic layer was dried over sodium sulfate, and concentrated. The residue was then distilled (149°-151° C. @ 25 mm)(short path column) to afford 95.6 g (94%) of m-methoxy-1-methyl-benzyl alcohol as a clear oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][C:26]([N+:29]([O-])=O)=[C:25]([O:32][CH3:33])[CH:24]=3)[CH2:19][CH2:18]2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C>[Zn].C(O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][C:26]([NH2:29])=[C:25]([O:32][CH3:33])[CH:24]=3)[CH2:19][CH2:18]2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(N2CCC(N3CCN(C(=O)OCc4ccccc4)CC3)CC2)ccc1[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCO
Product: COc1cc(N2CCC(N3CCN(C(=O)OCc4ccccc4)CC3)CC2)ccc1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 83 %

Procedure:
A mixture of 4-[1-(3-Methoxy-4-nitro-phenyl)-piperidin-4-yl]-piperazine-1-carboxylic acid benzyl ester (0.20 g, 0.44 mmol), Acetic acid (2 mL, 30 mmol), Ethanol (2 mL) and Zinc (0.20 g, 3.0 mmol) was stirred at room temperature for 3 hours. The reaction was filtered and evaporated. To the residue was added a saturated sodium bicarbonate solution and DCM, separated, dried and evaporated to give 4-[1-(4-Amino-3-methoxy-phenyl)-piperidin-4-yl]-piperazine-1-carboxylic acid benzyl ester as a dark blue solid (0.155 g, 82%). LCMS (m/e) 424 (M); 1H-NMR (DMSO-d6, 400 MHz) δ7.387.36 (m, 5H), 6.48 (s, 2H), 6.13 (s, 1H), 5.07 (s, 2H), 4.20 (br, 2H), 3.73 (s, 3H), 3.39 (m, 6H), 1.80 (m, 2H, 0.80 (m, 2H).
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]2[CH:14]=[CH:13][C:12]([CH:15]([CH3:20])[C:16]([O:18]C)=[O:17])=[CH:11][C:6]=2[C:7](=[O:10])[C:8]=1[CH3:9])[CH3:2].C(=O)(O)[O-].[Na+]>C(O)C.O>[CH2:1]([C:3]1[O:4][C:5]2[CH:14]=[CH:13][C:12]([CH:15]([CH3:20])[C:16]([OH:18])=[O:17])=[CH:11][C:6]=2[C:7](=[O:10])[C:8]=1[CH3:9])[CH3:2]
Reactant: CCc1oc2ccc(C(C)C(=O)OC)cc2c(=O)c1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCc1oc2ccc(C(C)C(=O)O)cc2c(=O)c1C
Yield: 42.2 %

Procedure:
A solution of methyl 2-(2-ethyl-3-methyl-4-oxo-4H-1-benzopyran-6-yl)propionate (1 g) in ethanol (120 mls), and sodium bicarbonate (1 g) in water (30 mls) was refluxed for 20 hours. The ethanol was removed on a `Rotavapor` and the residue was washed with ether (3×50 mls). After acidification with dilute hydrochloric acid, the aqueous phase was extracted with ethyl acetate (3×50 mls), which was washed with brine solution (3×30 mls), dried over anhydrous magnesium sulphate and evaporated to yield an off-white solid. This was recrystallised from ethyl acetate to yield the product as a pale yellow solid (0.4 g; 42%), mp 196°-198° C.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([C:14]#[CH:15])[O:7][C@H:6]1[N:16]1[CH:24]=[N:23][C:22]2[C:17]1=[N:18][CH:19]=[N:20][C:21]=2Cl)(=[O:3])[CH3:2].[OH:26][N:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[N:29]=[N:28]1.Cl>CN(C=O)C>[C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([C:14]#[CH:15])[O:7][C@H:6]1[N:16]1[CH:24]=[N:23][C:22]2[C:17]1=[N:18][CH:19]=[N:20][C:21]=2[O:26][N:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[N:29]=[N:28]1)(=[O:3])[CH3:2]
Reactant: On1nnc2ccccc21
Reactant: C#C[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Cl
Solvent: CN(C)C=O
Product: C#C[C@H]1O[C@@H](n2cnc3c(On4nnc5ccccc54)ncnc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Yield: 112 %

Procedure:
(2R,3R,4R,5R)-4-(acetyloxy)-2-(6-chloro-9H-purin-9-yl)-5-ethynyltetrahydrofuran-3-yl acetate (104 mg) was treated with 1-hydroxybenzotriazole (136 mg) in dry DMF (3 ml) for 45 h at 22° C. The mixture was poured into ice cooled 1M hydrochloric acid (50 ml) and extracted with dichloromethane (3×25 ml); the organic layers were washed with water (20 ml) and saturated aqueous sodium bicarbonate (20 ml), dried (MgSO4) and evaporated in vacuo to give a colourless gum (148 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]([C:15]2[N:23]3[C:18]([C:19]([NH2:24])=[N:20][CH:21]=[N:22]3)=[C:17](Br)[CH:16]=2)=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:26]([N:33]1[CH:41]=[C:40]2[C:35]([CH:36]=[C:37](B3OC(C)(C)C(C)(C)O3)[CH:38]=[CH:39]2)=[N:34]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.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>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]([C:15]2[N:23]3[C:18]([C:19]([NH2:24])=[N:20][CH:21]=[N:22]3)=[C:17]([C:37]3[CH:38]=[CH:39][C:40]4[C:35]([CH:36]=3)=[N:34][N:33]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:41]=4)[CH:16]=2)=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2cc(Br)c3c(N)ncnn23)C1
Reactant: CC1(C)OB(c2ccc3cn(Cc4ccccc4)nc3c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C(=O)c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)C1
Temperature: 110 °C
Yield: 66.6 %

Procedure:
To a stirred solution 3-(4-amino-5-bromo-pyrrolo[2,1-f][1,2,4]triazine-7-carbonyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (1.33 g, 3.24 mmol), intermediate C (1.63 g, 4.86 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.37 g, 0.32 mmol) in degassed DMF (35 mL) was added aqueous Na2CO3 (2M, 5.34 mL). The resulting mixture was heated at 110° C. for 3 h and then cooled to rt. The reaction mixture was diluted with EtOAc and filtered through a Celite® pad. The organic layer was separated and concentrated in vacuo. The residue was purified by silica-gel column using a gradient of 50 to 100% EtOAc in hexanes to afford 1.16 g (66%) of the desired product. 1H-NMR (CD3OD-d4) 8.39 (s, 1H), 8.05 (s, 1H), 7.87 (dd, 1H), 7.70 (s, 1H), 7.50 (s, 1H), 7.37-7.29, (m, 5 H), 7.24 (dd, 1 H), 5.67 (s, 1 H), 4.47-4.39 (m, 2 H), 3.71-3.59 (m, 2 H), 2.34-2.12 (m, 2 H), 1.45 (s, 1H); LC-MS [M+H]+=537.9, RT=3.36 min.
Reaction SMILES: [C:1](=[O:27])(OC1C=CC([N+]([O-])=O)=CC=1)[O:2][CH:3](C(OC(C)(C)C)=O)[CH:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.CCN(C(C)C)C(C)C.Cl.Cl.[CH3:39][C:40]1[CH:45]=[CH:44][C:43]([N:46]2[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)=[CH:42][CH:41]=1>CN(C=O)C>[CH3:39][C:40]1[CH:41]=[CH:42][C:43]([N:46]2[CH2:51][CH2:50][N:49]([C:1]([O:2][CH2:3][CH:4]3[CH2:5][CH2:6][NH:7][CH2:8][CH2:9]3)=[O:27])[CH2:48][CH2:47]2)=[CH:44][CH:45]=1
Reactant: Cc1ccc(N2CCNCC2)cc1
Reactant: CC(C)(C)OC(=O)C(OC(=O)Oc1ccc([N+](=O)[O-])cc1)C1CCNCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(N2CCN(C(=O)OCC3CCNCC3)CC2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 50.4 %

Procedure:
(tert-Butoxycarbonyl)piperidin-4-ylmethyl 4-nitrophenyl carbonate (Intermediate 2; 3.80 g, 10.0 mmol) was dissolved in DMF (100 mL). DIPEA (6.10 mL, 35.0 mmol) and 4-(4-methylphenyl)piperazine dihydrochloride (2.49 g, 10.0 mmol) were added. The reaction mixture was stirred at room temperature for 4 hours and then concentrated in vacuo. The resulting residue was dissolved in EtOAc (300 mL) and washed with a 1 M aq Na2CO3 solution (6×200 mL), 10% citric acid solution (50 mL), brine (50 mL), dried (MgSO4) and concentrated in vacuo. The residue was dissolved in a mixture of DCM (100 mL) and TFA (25 mL), stirred for 48 hours and then concentrated in vacuo. The residue was purified by reverse phase column chromatography (gradient eluting with MeOH in water, with 1% formic acid in each solvent, 0-30%). The resulting residue was dissolved in DCM (70 mL) and stirred with solid K2CO3 for 20 minutes, filtered and concentrated in vacuo to give piperidin-4-ylmethyl 4-(4-methylphenyl)piperazine-1-carboxylate (1.60 g, 44.6%) as a pale yellow solid.
Reaction SMILES: [CH2:1]([NH:13][C:14](=[O:36])[C:15]1[CH:20]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=2)[C:18]([O:31][CH2:32][CH2:33]Br)=[C:17]([Br:35])[CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[NH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH2:1]([NH:13][C:14]([C:15]1[CH:20]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:28])[F:29])[CH:22]=2)[C:18]([O:31][CH2:32][CH2:33][N:37]2[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)=[C:17]([Br:35])[CH:16]=1)=[O:36])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: C1COCCN1
Reactant: CCCCCCCCCCCCNC(=O)c1cc(Br)c(OCCBr)c(-c2cccc(C(F)(F)F)c2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCCCCCCCCCNC(=O)c1cc(Br)c(OCCN2CCOCC2)c(-c2cccc(C(F)(F)F)c2)c1
Yield: 100.3 %

Procedure:
To a solution of N-dodecyl-3-bromo-4-(2-bromoethoxy)-5-(m-trifluoromethylphenyl)-benzamide (0.294 g, 0.46 mmol, 1 eq) in CH3CN (4 mL) was added morpholine (0.50 mL, 0.57 mmol 1.24 eq) and K2CO3 (0.509 g, 3.68 mmol, 8 eq). The reaction was heated at reflux overnight. The solids were filtered off and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (50% EtOAc:hexane) to afford the title compound (0.296 g, 100%) as a colorless oil. 1H NMR (DMSO-d6) δ 8.53 (bt, 1H); 8.11 (d, 1H); 7.88-7.83 (m, 3H); 7.78 (d, 1H); 7.72 (dd, 1H); 3.63 (dd, 2H); 3.40 (dd, 4H); 3.21 (dd, 2H); 2.38 (dd, 2H); 2.15 (dd, 4H); 1.48 (dd, 2H); 1.22 (m, 18H); 0.82 (t, 3H); IR (KBr) 3400, 2900, 2800, 1630, 1540, 1450, 1330, 1310, 1170, 1120, 700 cm−1; mass spectrum [(+)APCI], m/z 641/643 (M+H)+; Anal. Calcd. for C31H34BrF3N2O4: C, 59.90; H, 6.91; N, 4.37, Found: C, 58.58; H, 7.01; N, 4.18.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:16]([C:18]2[CH:23]=[CH:22][C:21]([O:24]C3CCCCO3)=[CH:20][CH:19]=2)=O)[CH:5]=[CH:6][C:7]=1[C:8]#[C:9][CH2:10][N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1.[C:31]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)(=O)[CH2:32][CH3:33]>>[F:1][C:2]1[CH:3]=[C:4]([C:16]([C:18]2[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=2)=[C:31]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:32][CH3:33])[CH:5]=[CH:6][C:7]=1[C:8]#[C:9][CH2:10][N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CCC(=O)c1ccccc1
Reactant: O=C(c1ccc(OC2CCCCO2)cc1)c1ccc(C#CCN2CCCC2)c(F)c1
Product: CCC(=C(c1ccc(O)cc1)c1ccc(C#CCN2CCCC2)c(F)c1)c1ccccc1
Yield: 35868 %

Procedure:
Following general procedure of McMurry reaction as described in example 1, step B, (3-fluoro-4-(3-(pyrrolidin-1-yl)prop-1-ynyl)phenyl)(4-(tetrahydro-2H-pyran-2-yloxy)phenyl)methanone (155 mg, 0.38 mmol) was reacted with propiophenone (152 mg, 1.13 mmol) to give 58 g desired product (36% yield, Z/E=1/1). m/z=426[M+1]+.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:8]([C:12]1[N:13]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]3[N:38]([C:39]([C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)[C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[N:37]=[N:36][N:35]=3)=[CH:24][CH:23]=2)[C:14]([C:18]([OH:20])=[O:19])=[C:15]([Cl:17])[N:16]=1)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:8]([C:12]1[N:13]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]3[N:38]([C:39]([C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=4)([C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=4)[C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)[N:37]=[N:36][N:35]=3)=[CH:26][CH:27]=2)[C:14]([C:18]([O:20][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:19])=[C:15]([Cl:17])[N:16]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCOC(=O)CBr
Reactant: CCCCc1nc(Cl)c(C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCc1nc(Cl)c(C(=O)OCC(=O)OCC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ethyl bromoacetate (263 μL, 2.37 mmol) was added to a solution of 2-butyl-4-chloro-1-{[2′-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-1H-imidazole-5-carboxylic acid (Intermediate 4, 1000 mg, 1.48 mmol), and potassium carbonate (347 mg, 2.51 mmol) in N,N-dimethylformamide (10 mL). The solution was stirred for 2 hours at room temperature. Water was added and the solution was extracted with diethyl ether (2×). The organic layers were dried (magnesium sulfate), filtered, and concentrated in vacuo. The residue was used crude in the following step. LC-MS: m/z 787.1 (M+Na).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([CH:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29]4[NH:33][C:32]5[CH:34]=[CH:35][C:36]([CH3:38])=[CH:37][C:31]=5[N:30]=4)[CH:23]=3)[CH2:18][CH2:17]2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C>Cl.CCOCC>[F:28][C:25]1[CH:26]=[CH:27][C:22]([N:19]2[CH2:18][CH2:17][CH:16]([C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[O:15])[CH2:21][CH2:20]2)=[CH:23][C:24]=1[C:29]1[NH:33][C:32]2[CH:34]=[CH:35][C:36]([CH3:38])=[CH:37][C:31]=2[N:30]=1
Reactant: Cc1ccc2[nH]c(-c3cc(N4CCC(C(=O)N5CCN(C(=O)OC(C)(C)C)CC5)CC4)ccc3F)nc2c1
Agent: Cl
Solvent: CCOCC
Product: Cc1ccc2[nH]c(-c3cc(N4CCC(C(=O)N5CCNCC5)CC4)ccc3F)nc2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 118.6 %

Procedure:
Method I—Step b A mixture of 4-{1-[4-Fluoro-3-(5-methyl-1H-benzoimidazol-2-yl)-phenyl]-piperidine-4-carbonyl}-piperazine-1-carboxylic acid tert-butyl ester (0.02 g, 0.04 mmol) in 2M HCl in Et2O (3 mL) was stirred for 2 days at room temperature, then solvent was removed and the crude filtered through an NH2 cartridge (eluent EtOAc), to obtain 0.02 g of the title compound with quantitative yield.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH:4]([CH2:10][CH2:11][CH3:12])[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[CH:13](O)=[O:14]>>[CH3:1][N:2]([CH2:3][CH:4]([CH2:10][CH2:11][CH3:12])[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH:13]=[O:14]
Reactant: CCCCCC(CCC)CNC
Reactant: O=CO
Product: CCCCCC(CCC)CN(C)C=O
Temperature: 60 °C

Procedure:
A total amount of 846 g (4.81 moles) of N-methyl-N-(2-propylheptyl)-amine was added to a 2 l round bottomed flange flask equipped with a condenser. Formic acid was charged into a dropping funnel in an amount of 223.3 g (4.80 moles) and added drop wise to the round bottomed flange flask over a time period of 1 hour during heating and stirring with a magnetic stirrer. The final temperature was set to 180° C., while the boiling point of the initial reaction mixture was ˜125° C. Water was distilled off and collected in a round bottomed receiver flask and thereby removed from the reaction medium. During the reaction the boiling point of the reaction medium rose continuously. The reaction was performed at atmospheric pressure for a total time of 3.5 hours. Titration of remaining amine was performed to monitor the reaction. When the amine value did not decrease anymore, the remaining unreacted material was removed by gently pulling vacuum to 100 mbar for two hours. The reaction mixture was cooled to 60° C. before breaking the vacuum.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([CH2:13][P:14]([O:18][CH3:19])([O:16][CH3:17])=[O:15])=[CH:5]2.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:38]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:38][CH2:12][C:7]1[C:6]([CH2:13][P:14]([O:16][CH3:17])([O:18][CH3:19])=[O:15])=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=2)[N:8]=1
Reactant: COP(=O)(Cc1cc2cc(Cl)ccc2nc1C)OC
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COP(=O)(Cc1cc2cc(Cl)ccc2nc1CBr)OC
Yield: 73.4 %

Procedure:
A solution of 6-chloro-3-(dimethylphosphonomethyl)-2-methylquinoline (0.85 g, 2.7 mmol) in carbon tetrachloride (40 ml) was treated with benzoyl peroxide (100 mg) followed by N-bromosuccinimide (0.50 g, 2.8 mmol). The reaction mixture was refluxed for 4 hours, filtered and concentrated in vacuo. The residue was flash chromatographed on silica gel with ethyl acetate as the eluent to give 0.75 g of 2-bromomethyl-6-chloro-3-(dimethylphosphonomethyl)quinoline.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[CH2:4]Cl.[C:7]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:12]=[CH:11][C:10]([CH2:13][C@@H:14]([NH:23]C(OC(C)(C)C)=O)[CH2:15][C@:16]([CH2:21][OH:22])([CH3:20])[C:17]([OH:19])=[O:18])=[CH:9][CH:8]=1.CCN(CC)CC>CC(C)=O>[CH3:1][O:2][C:3]([CH2:4][O:19][C:17](=[O:18])[C@@:16]([CH2:21][OH:22])([CH3:20])[CH2:15][C@H:14]([NH2:23])[CH2:13][C:10]1[CH:11]=[CH:12][C:7]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:8][CH:9]=1)=[O:6]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(-c2ccccc2)cc1)C[C@@](C)(CO)C(=O)O
Reactant: COC(=O)CCl
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: COC(=O)COC(=O)[C@](C)(CO)C[C@H](N)Cc1ccc(-c2ccccc2)cc1

Procedure:
Chloroacetic acid methyl ester (34 μL, 387 μmol) was added to a mixture of (2S,4R)-5-biphenyl-4-yl-4-t-butoxycarbonylamino-2-hydroxymethyl-2-methyl-pentanoic acid (100 mg, 242 μmol) and Et3N (35 μL, 254 μmol) in acetone (10 mL). The mixture was refluxed for 24 hours and the reaction monitored for completion. When the reaction was complete, the product was purified ((Interchim reverse phase chromatography column) the solvent was removed under vacuum to yield (2S,4R)-4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid methoxycarbonylmethyl ester.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].Cl.[O:21]1[CH2:26][CH2:25][N:24]([CH2:27][C:28](O)=[O:29])[CH2:23][CH2:22]1>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:19])[N:2]([NH:1][C:28](=[O:29])[CH2:27][N:24]3[CH2:25][CH2:26][O:21][CH2:22][CH2:23]3)[N:11]=2)=[CH:13][CH:14]=1
Reactant: O=C(O)CN1CCOCC1
Reactant: Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O
Agent: Cl
Product: O=C(CN1CCOCC1)Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O

Procedure:
The product of Example 86A and 2-morpholinoacetic acid hydrochloride were treated using a method similar to that described in Example 57 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.42-8.46 (m, 1H), 7.96-8.08 (m, 2H), 7.75-7.79 (m, 1H), 7.64-7.69 (m, 4H), 4.27-4.28 (m, 2H), 3.79-3.94 (m, 4H), 3.34-3.38 (m, 4H); MS (APCI+) M/Z 399 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:43]=[CH:42][N:41]=[C:40]([N:44]3[CH2:49][CH2:48][O:47][CH2:46][CH2:45]3)[CH:39]=2)[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:43]=[CH:42][N:41]=[C:40]([N:44]3[CH2:45][CH2:46][O:47][CH2:48][CH2:49]3)[CH:39]=2)[CH:33]=1)=[O:31])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccnc(N3CCOCC3)c2)c1
Product: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(N4CCOCC4)c3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-ethoxy-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J8) (240 mg, 0.75 mmol) and 3-[3-(2-morpholin-4-yl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K62) (286 mg, 0.75 mmol) according to the general procedure M. Obtained as a white solid (259 mg, 55%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12]2[C:13]3[CH2:20][CH2:19][CH:18]([OH:21])[C:14]=3[CH:15]=[N:16][CH:17]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].C(N(CC)C(C)C)(C)C.[C:31](Cl)(=[O:34])[CH2:32][CH3:33].[OH-].[Na+]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:12]2[C:13]3[CH2:20][CH2:19][CH:18]([O:21][C:31](=[O:34])[CH2:32][CH3:33])[C:14]=3[CH:15]=[N:16][CH:17]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9]
Reactant: OC1CCc2c(-c3ccc(C(F)(F)F)c(F)c3)cncc21
Reactant: CCC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCC(=O)OC1CCc2c(-c3ccc(C(F)(F)F)c(F)c3)cncc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 11.2 %

Procedure:
A solution of (rac)-4-(3-fluoro-4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-ol (example 82) (24 mg, 0.081 mmol) and N,N-diisopropylethylamine (0.028 mL, 0.162 mmol) in DMF (0.2 mL) was treated with propionyl chloride (0.021 mL, 0.243 mmol) and the reaction mixture stirred at room temperature. After 15 h, another aliquot of propionyl chloride (0.021 mL, 0.243 mmol) was added, the temperature increased to 50° C. and stirring continued for 2 h. The crude reaction mixture was poured into a 1 M solution of sodium hydroxide (10 mL) and extracted with ethyl acetate (2×15 mL). The combined organic extracts were washed with a sat. solution of sodium chloride (10 mL), dried (Na2SO4), and concentrated under reduced pressure. Purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 3.2 mg (11%) of the title compound as a light brown solid. MS: 354.5 (M+H)+.
Reaction SMILES: [N:1]1[O:5][N:4]=[C:3]2[CH:6]=[C:7]([CH:10]3[N:15]([C:16]([O:18][C:19]4[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=4)=[O:17])[C:14]([O:28]C)=[N:13][C:12]([CH3:30])=[C:11]3[C:31]([O:33][CH3:34])=[O:32])[CH:8]=[CH:9][C:2]=12.[Br:35]Br>C(Cl)(Cl)Cl>[N:1]1[O:5][N:4]=[C:3]2[CH:6]=[C:7]([CH:10]3[N:15]([C:16]([O:18][C:19]4[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=4)=[O:17])[C:14](=[O:28])[NH:13][C:12]([CH2:30][Br:35])=[C:11]3[C:31]([O:33][CH3:34])=[O:32])[CH:8]=[CH:9][C:2]=12
Reactant: COC(=O)C1=C(C)N=C(OC)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C1c1ccc2nonc2c1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: COC(=O)C1=C(CBr)NC(=O)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C1c1ccc2nonc2c1
Reaction time: 1.5 h
Yield: 90.9 %

Procedure:
Into a well-stirred solution of 6-(benzofurazan-5-yl)-1,6-dihydro-2-methoxy-5-methoxycarbonyl-4-methyl-1-[(4-nitrophenyl-oxy)carbonyl]pyrimidine (0.310 mmol, 0.140 g) in 1.5 mL of chloroform was added a solution of bromine (0.310 mmol, 0.020 mL) in 1.5 mL of chloroform at 0° C. and the solution was allowed to attain room temperature over 1.5 h. The solvent was removed in vacuo and the residue was again dissolved in CHCl3 (10 mL) and washed with brine. The organic layer was separated, dried over Na2SO4, filtered and the solvent was removed in vacuo to obtain 0.15 g (88% yield) of 6-(benzofurazan-5-yl)-1,6-dihydro-2-oxo-5-methoxycarbonyl-4-bromomethyl-1-[(4-nitrophenyl-oxy)carbonyl]pyrimidine as a yellow foam. The crude product was used in the next step without purification. 1H NMR (CDCl3) δ 3.79 (s, 3 H), 4.72 (ABq, 2 H), 6.47 (s, 1 H), 7.37 (d, J=9.1 Hz, 2 H), 7.51 (d, J=7.8 Hz, 1 H), 7.80 (s, 1 H), 7.92 (d, J=9.1 Hz, 1 H), 8.30 (d, J=9.1 Hz, 2 H).