Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:36])[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[CH2:8][C:9]1[N:10]([CH3:35])[C:11]2[C:16]([N:17]=1)=[C:15]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[N:14]=[C:13]([N:24]1[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[N:26]=[C:25]1[CH2:33][CH3:34])[N:12]=2.[C:37](O)(=[O:41])[C@@H:38]([CH3:40])[OH:39].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>C(Cl)Cl>[CH2:33]([C:25]1[N:24]([C:13]2[N:12]=[C:11]3[C:16]([N:17]=[C:9]([CH2:8][N:3]4[CH2:4][CH2:5][N:6]([C:37](=[O:41])[C@H:38]([OH:39])[CH3:40])[CH2:7][C:2]4([CH3:1])[CH3:36])[N:10]3[CH3:35])=[C:15]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[N:14]=2)[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[N:26]=1)[CH3:34]
Reactant: C[C@@H](O)C(=O)O
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCNCC3(C)C)n(C)c2n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN(C(=O)[C@@H](C)O)CC3(C)C)n(C)c2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 32.9 %

Procedure:
A mixture of 8-(2,2-dimethylpiperazin-1-ylmethyl)-2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine (100 mg, 0.20 mmol), D-Lactic acid (20 mg, 0.22 mmol), HATU (85 mg, 0.22 mmol) and DIPEA (40 μL, 0.23 mmol) in DCM (2 mL) was allowed to stir at r.t. for 16 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was purified by column chromatography (Si—PCC, MeOH:DCM, 2%) affording 722 as a white solid (37 mg, 33%). LCMS (method I): RT 2.90 min, [M+H]+ 562.2. 1H NMR (CDCl3, 400 MHz): δ 8.04-7.99 (1 H, m), 7.77-7.76 (1 H, m), 7.35-7.25 (2 H, m), 4.47-4.45 (1 H, m), 4.34 (4 H, brd s), 4.02-3.98 (1 H, m), 3.91 (3 H, s), 3.86 (4 H, t, J=4.67 Hz), 3.82-3.68 (2 H, m), 3.50-3.49 (1 H, m), 3.40-3.31 (3 H, m), 3.27-3.16 (1 H, m), 2.57-2.55 (2 H, m), 1.45 (3 H, t, J=7.47 Hz), 1.39-1.28 (4 H, m), 1.27-1.15 (5 H, m)
Reaction SMILES: Br[C:2]1[O:3][C:4]2[C:16]([C:17]([OH:19])=[O:18])=[CH:15][C:14]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:13][C:5]=2[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[N+:26]([O-])([OH:28])=[O:27].N([O-])=O.[Na+].O>C(O)(=O)C>[C:7]1([C:6]2[C:5]3[CH:13]=[C:14]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:15]=[C:16]([C:17]([OH:19])=[O:18])[C:4]=3[O:3][C:2]=2[N+:26]([O-:28])=[O:27])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(O)c1cc(-c2ccccc2)cc2c(-c3ccccc3)c(Br)oc12
Reactant: O=[N+]([O-])O
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1cc(-c2ccccc2)cc2c(-c3ccccc3)c([N+](=O)[O-])oc12

Procedure:
A solution of 6 g. (0.018 mole) of the product of step E in hot acetic acid is treated with 6 ml. of 70 percent nitric acid while the solution is maintained at about 80° C. Sodium nitrite (2.7 g., 2 equivalents) is added gradually, and the mixture is heated on a steam bath for 45 minutes. The mixture is then poured into 500 ml. of water. The solid is filtered, recrystallized twice from acetone,, then from an ethyl acetate-hexane mixture to provide yellow crystals of 3,5-diphenyl-2-nitrobenzofuran-7-carboxylic acid, m.p. 207°-209° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:34])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]=[C:17]3[C:27]4[C:22](=[N:23][CH:24]=[CH:25][CH:26]=4)[O:21][C:20]4[CH:28]=[CH:29][CH:30]=[C:31]([C:32]#[N:33])[C:19]=4[CH2:18]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[N-:35]=[N+:36]=[N-:37].[Na+].[Cl-].[NH4+].O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:34])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]=[C:17]3[C:27]4[C:22](=[N:23][CH:24]=[CH:25][CH:26]=4)[O:21][C:20]4[CH:28]=[CH:29][CH:30]=[C:31]([C:32]5[NH:37][N:36]=[N:35][N:33]=5)[C:19]=4[CH2:18]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1cccc2c1CC(=CCCN1CCC(O)(c3ccc(Cl)cc3)CC1)c1cccnc1O2
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: OC1(c2ccc(Cl)cc2)CCN(CCC=C2Cc3c(cccc3-c3nnn[nH]3)Oc3ncccc32)CC1
Temperature: 100 °C
Reaction time: 36 h
Yield: 73.3 %

Procedure:
To a solution of the product of Example 364 (1.0 g) in DMF (10 ml) were added sodium azide (0.69 g) and ammonium chloride (0.56 g) and the mixture stirred at 100° C. for 36 hour. Water was added to the reaction mixture, and the precipitate was filtered and washed with ethanol to give the titled compound (800 mg).
Reaction SMILES: [O:1]1[C:7]2[CH:8]=[CH:9][C:10]([CH2:12][CH2:13][CH:14]([NH2:18])[CH:15]([CH3:17])[CH3:16])=[CH:11][C:6]=2[O:5][CH2:4][CH2:3][CH2:2]1.[CH3:19][CH:20]([CH2:24][NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:21](O)=[O:22].Cl.C(N=C=NCCCN(C)C)C.O>CN(C1C=CN=CC=1)C.ClCCl>[CH3:19][CH:20]([CH2:24][NH:25][C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27])[C:21]([NH:18][CH:14]([CH:15]([CH3:16])[CH3:17])[CH2:13][CH2:12][C:10]1[CH:9]=[CH:8][C:7]2[O:1][CH2:2][CH2:3][CH2:4][O:5][C:6]=2[CH:11]=1)=[O:22]
Reactant: CC(CNC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)C(N)CCc1ccc2c(c1)OCCCO2
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CC(CNC(=O)OC(C)(C)C)C(=O)NC(CCc1ccc2c(c1)OCCCO2)C(C)C
Reaction time: 8 h

Procedure:
50 mg of (±)-1-(3,4-dihydro-2H-1,5-benzodioxepine-7-yl)-4-methylpentan-3-ylamine was mixed with of (±)-2-Methyl-3-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid (25 mg), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (53 mg), and DMAP (33 mg) in dichloromethane (5 ml) and stirred overnight. Water (5 ml) was added, and the reaction mixture was extracted with ethyl acetate (5 ml three times). The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by flash chromatography on silica (20% ethyl acetate in hexane) yielded a resin: MS (m+1)=435.6.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([CH2:13][CH2:12][CH2:11][CH2:10]2)[C:2]1=[O:14].C(N(CC)CC)C.[C:22]([O:26][C:27]([C:29]1([CH2:35][N:36]2[CH2:41][CH2:40][CH:39]([CH2:42][NH2:43])[CH2:38][CH2:37]2)[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].[C:44]([O-])(O)=[O:45].[Na+]>C(Cl)Cl>[O:14]=[C:2]1[C:3]2([CH2:13][CH2:12][CH2:11][CH2:10]2)[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:1]1[C:44]([NH:43][CH2:42][CH:39]1[CH2:40][CH2:41][N:36]([CH2:35][C:29]2([C:27]([O:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:28])[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)[CH2:37][CH2:38]1)=[O:45]
Reactant: CC(C)(C)OC(=O)C1(CN2CCC(CN)CC2)CCOCC1
Reactant: O=C([O-])O
Reactant: O=C1Nc2ccccc2C12CCCC2
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)C1(CN2CCC(CNC(=O)N3C(=O)C4(CCCC4)c4ccccc43)CC2)CCOCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
To a stirred solution of spiro[cyclopentane-1,3′-indol]-2′(1′H)-one (600 mg, 3.2 mmol, Howard, Harry R. et al., J. Med. Chem., 1996, 39, 143) and triethylamine (972 mg, 9.6 mmol) in CH2Cl2 (20 mL) was added 4-nitrochloroformate (677 mg, 3.4 mmol) at room temperature, and stirred at ambient temperature for 3 h. Then, a solution of tert-butyl 4-{[4-(aminomethyl)piperidin-1-yl]methyl}tetrahydro-2H-pyran-4-carboxylate (1.0 g, 3.2 mmol, step 5 of Example 1) in CH2Cl2 (5 mL) was added at room temperature, and stirred for 18 h. Then, sat. NaHCO3 aq. (20 mL) was added, extracted with CH2Cl2 (30 mL×3), dried over MgSO4, filtered and concentrated gave yellow brown oil. The residue was chromatographed on a column of aminopropyl-silica gel eluting with hexane/ethyl acetate (11:1) to give 1.3 g (75%) of the title compound as clear yellow oil.
Reaction SMILES: [CH2:1]([C:5]1([CH2:32][CH2:33][CH2:34][CH3:35])[C:17]2[CH:16]=[C:15]([N:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:14]=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][C:8](Br)=[CH:9][CH:10]=2)[CH2:2][CH2:3][CH3:4].C([Li])CCC.[B:41](OC)([O:44]C)[O:42]C.Cl>O.C1COCC1>[CH2:1]([C:5]1([CH2:32][CH2:33][CH2:34][CH3:35])[C:17]2[CH:16]=[C:15]([N:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:14]=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][C:8]([B:41]([OH:44])[OH:42])=[CH:9][CH:10]=2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1(CCCC)c2cc(Br)ccc2-c2ccc(N(c3ccccc3)c3ccccc3)cc21
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCCCC1(CCCC)c2cc(B(O)O)ccc2-c2ccc(N(c3ccccc3)c3ccccc3)cc21
Temperature: -30 °C
Reaction time: 1 h
Yield: 79.4 %

Procedure:
To a dry 100 mL two-neck flask containing 1.3 g (2.47 mmol) of compound 2 and 30 mL of dry THF was dropwise added 2.3 mL (3.71 mmol) of 1.6 M of n-butyl lithium under N2 at −78° C. while maintaining a good stirring. After stirring for 1 h, trimethyl borate (0.4 mL, 3.71 mmol) was added in one portion. The reaction mixture was then stirred for 1 h at −78° C. When the mixture was naturally warmed to −30° C., water and HCl (3 M) were added. Then the solution mixture was poured into water wad extracted with ethyl acetate (3×50 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and evaporated to dryness under 35° C. The crude product was purified by silica gel column chromatography using dichloromethane and petroleum ether/ethyl acetate as eluent affording a light-yellow solid (0.96 g, 79%). 1H NMR (400 MHz, DMSO-d6, δ) 8.02 (s, 2H), 7.80 (s, 1H), 7.77 (d, J=7.6 Hz, 1H), 7.71 (d, J=8.4 Hz, 1H), 7.27 (t, J=7.6 Hz, 1H), 7.08 (d, J=1.6 Hz, 1H), 6.93-7.01 (m, 6H), 6.91 (d, J=2.0 Hz, 1H), 1.79-1.88 (m, 4H), 0.95-1.04 (m, 4H), 0.65 (t, J=7.4 Hz, 6H), 0.50-0.58 (m, 4H). 13C NMR (100 MHz, DMSO-d6, δ) 152.1, 148.9, 147.4, 146.8, 142.1, 136.1, 133.1, 129.4, 129.3, 128.2, 123.3, 122.7, 121.1, 119.1, 118.3, 54.3, 39.2, 25.8, 22.4, 13.8. MS (FAB) m/z 489.7 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[C:11](=[CH:14]/[C:15]2[S:16][C:17]([N+:20]([O-])=O)=[CH:18][CH:19]=2)/[C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].O.O.[Cl-].[Ca+2].[Cl-]>C(O)C.[Zn]>[NH2:20][C:17]1[S:16][C:15](/[CH:14]=[C:11](/[C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)\[C:12]#[N:13])=[CH:19][CH:18]=1
Reactant: COc1ccc(/C(C#N)=C/c2ccc([N+](=O)[O-])s2)cc1OC
Agent: [Ca+2]
Agent: [Cl-]
Agent: [Zn]
Solvent: O
Solvent: CCO
Product: COc1ccc(/C(C#N)=C/c2ccc(N)s2)cc1OC
Reaction time: 2 h
Yield: 12.2 %

Procedure:
Compound 1 (316 mg) was dissolved in ethanol (25 mL), and calcium chloride dihydrate (132 mg) and zinc powder (2.55 g) were added to the solution, followed by stirring for 2 hours under reflux. The reaction mixture was subjected to filtration by use of a celite pad, to thereby remove zinc powder, and the solvent was evaporated to dryness. The residue was purified by silica gel column chromatography (hexane-ethyl acetate), to thereby yield the target product (yield: 35 mg, 12%).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([OH:22])=O)[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH:25]1[CH2:30][CH2:29][CH:28]([OH:31])[CH2:27][CH2:26]1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>C(Cl)Cl.O>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([N:25]3[CH2:30][CH2:29][CH:28]([OH:31])[CH2:27][CH2:26]3)=[O:22])[N:14]=2)[CH:4]=[C:3]([C:2]([F:24])([F:23])[F:1])[CH:8]=1
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Reactant: OC1CCNCC1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: O=C(/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1)N1CCC(O)CC1
Reaction time: 0.5 h
Yield: 10.1 %

Procedure:
A 50-mL, 3-necked, round-bottomed flask was charged with a solution of (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (0.20 g) in CH2Cl2 (10 mL). Piperidin-4-ol (0.07 g, 1.2 eq.) was added and the solution was cooled to −60° C. for the addition of T3P (propyl phosphonic anhydride) (0.40 mL, 1.2 eq.) and DIPEA (0.19 mL, 2.0 eq.). The reaction mixture was stirred for 30 min before being poured into water (50 mL) and extracted with CH2Cl2 (2×50 mL). The combined organic layers were washed with aqueous saturated brine (50 mL), dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure (25° C., 20 mmHg). Purification by column chromatography using silica 60/120 and MeOH:CH2Cl2 as mobile phase. (desired compound started eluting using 3.0% MeOH/CH2Cl2) afforded 0.025 g (yield: 10%) of (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-1-(4-hydroxypiperidin-1-yl)prop-2-en-1-one. 1H NMR (400 MHz, CDCl3) δ, 8.75 (s, 1H), 8.58 (s, 2H), 7.93 (s, 1H), 7.08-7.11 (d, J=10.4 Hz, 1H), 6.01-6.04 (d, J=10.4 Hz, 1H), 4.02-4.14 (m, 1H), 3.98-4.01 (m, 1H), 3.78-3.85 (m, 1H), 3.47-3.52 (s, 1H), 3.32-3.38 (s, 1H), 1.96 (s, 1H), 1.83 (s, 1H), 1.27 (s, 1H), 0.90 (s, 1H); LCMS for Chemical Formula: C18H17F6N4O2 [M+H]+ 435.34. found 435.24 (RT 2.408 min, purity: 89.6%).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([C:8]2[C:9]([C:18]([F:21])([F:20])[F:19])=[N:10][NH:11][C:12]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:7])=[C:4]([N+:24]([O-])=O)[CH:3]=1.Cl.O>C(O)C.B#[Ni]>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([C:8]2[C:9]([C:18]([F:21])([F:19])[F:20])=[N:10][NH:11][C:12]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:7])=[C:4]([NH2:24])[CH:3]=1
Reactant: CCOC(=O)c1[nH]nc(C(F)(F)F)c1C(=O)c1ccc(Cl)cc1[N+](=O)[O-]
Agent: B#[Ni]
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1[nH]nc(C(F)(F)F)c1C(=O)c1ccc(Cl)cc1N
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 104 %

Procedure:
The freshly prepared nickel boride (1.06 g) was added to a solution of ethyl 4-(4-chloro-2-nitrobenzoyl)-3-trifluoromethyl-1H-pyrazole-5-carboxylate (437.0 mg, 1.116 mmol) in ethanol (20 mL) followed by addition of 1.0 N aqueous hydrochloric acid (5.0 mL). This mixture was stirred at 60° C. for 30 minutes and then at room temperature overnight (17 hours). The reaction mixture was poured into water (250 mL) and extracted with diethyl ether (2×250 mL). The organic extract was filtered to remove residual black solids, washed successively with water (250 mL) and saturated aqueous sodium chloride (250 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated by rotary evaporation to afford 0.42 g of greenish-yellow solid. This material was dissolved in ethyl acetate (50 mL) and preabsorbed onto 4.1 g of silica gel, which was then applied to the top of a 40 g (2.84×14.2 cm) silica gel flash chromatography column. The column was eluted with hexane-ethyl acetate (90:10 then 80:20) to give 235.6 mg (58.4%) of the title compound as a light yellow solid.
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([NH:16][CH2:17][C:18](O)=[O:19])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[NH2:16][CH2:17][CH2:18][OH:19].[CH:12]1[C:8]2[CH:9]=[CH:10][C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[CH2:6][C:7]=2[CH:15]=[CH:14][CH:13]=1
Reactant: O=C(O)CNC1c2ccccc2C=Cc2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C1=Cc2ccccc2Cc2ccccc21
Product: NCCO
Reaction time: 8 h

Procedure:
5-H-Dibenzo[a,d]cyclohepten-5-ylglycine (4.8g, Example 1c) was added in portions to a solution of lithium aluminium hydride (54ml of 1.0M solution) in 30ml dry THF at 0° C. The reaction was allowed to stand at room temperature overnight, quenched with 2N sodium hydroxide and poured through Celite. The filtrate was washed with water, dried over MgSO4 and solvent removed in vacuo to leave a residue which was induced to crystallised in ethyl acetate or dichloromethane to give 5H-dibenzo[a,d]cycloheptene glycinol. 1H NMR (360MHz, d4MeOH) δ 3.05-3.17 (2H, m), 3.29-3.33 (1H, m), 3.89-3.94 (1H, m), 6.90-6.97 (2H, m), 7.23-7.38 (8H, m).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([S:29][CH3:30])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22]([OH:24])=O)[C:13]=2[CH2:12][NH:11][C:10]1=[O:31].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:65][C:66]1[CH:72]=[CH:71][C:69]([NH2:70])=[CH:68][CH:67]=1>C(Cl)Cl.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([S:29][CH3:30])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22]([NH:70][C:69]3[CH:71]=[CH:72][C:66]([F:65])=[CH:67][CH:68]=3)=[O:24])[C:13]=2[CH2:12][NH:11][C:10]1=[O:31]
Reactant: Nc1ccc(F)cc1
Reactant: CSc1nc(-c2cc(C(=O)O)ccc2C)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CSc1nc(-c2cc(C(=O)Nc3ccc(F)cc3)ccc2C)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Yield: 91.6 %

Procedure:
To the solution of 3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylbenzoic acid (1.2 g, 2.71 mmol) in CH2Cl2 (80 mL) were added diisopropyl ethyl amine (0.96 mL, 5.5 mmol), HATU (1.044 g, 2.75 mmol) and 4-floroaniline (0.276 mL, 2.92 mmol). The reaction mixture was stirred over night. The reaction mixture was diluted with CH2Cl2 (50 mL) and water (50 mL) and shaked. The layers were separated and the organic layer was washed with brine (75 mL), dried over Na2SO4, filtered and concentrated. CombiFlash chromatography (load column with DCM, mobile phase EtOAc/Hexane) then provided the title compound as a white solid 1.33 g (92%). LC-MS m/z 536 (M+H)+.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][C:11]3[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:12]=3[N:13]=2)=[CH:5][CH:4]=1.[C:21]1([P:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1(C)C(C)=CC=CC=1>[Br-:1].[N+:18]([C:15]1[CH:16]=[CH:17][C:11]2[S:10][C:9]([C:6]3[CH:7]=[CH:8][C:3]([CH3:2])=[C:4]([P+:27]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:5]=3)=[N:13][C:12]=2[CH:14]=1)([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1ccc2sc(-c3ccc(CBr)cc3)nc2c1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1C
Product: Cc1ccc(-c2nc3cc([N+](=O)[O-])ccc3s2)cc1[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]

Procedure:
A stirred solution of 104.7 g (0.3 mole) of 2-(4-bromomethylphenyl)-5-nitrobenzthiazole and 78.6 g (0.3 mole) of triphenylphosphine in xylene is heated at reflux for 19 hours. Compound B then is isolated by filtration, washed with additional portions of xylene, and dried.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([C:9]2[S:13][C:12]([C:14](=[O:16])[CH3:15])=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[Cl:19][C:20]1[C:27]([Cl:28])=[C:26]([OH:29])[CH:25]=[CH:24][C:21]=1[CH:22]=O>>[Cl:19][C:20]1[C:27]([Cl:28])=[C:26]([OH:29])[CH:25]=[CH:24][C:21]=1[CH:22]=[CH:15][C:14]([C:12]1[S:13][C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:17])([F:1])[F:18])[CH:4]=2)=[CH:10][CH:11]=1)=[O:16]
Reactant: O=Cc1ccc(O)c(Cl)c1Cl
Reactant: CC(=O)c1ccc(-c2cccc(C(F)(F)F)c2)s1
Product: O=C(C=Cc1ccc(O)c(Cl)c1Cl)c1ccc(-c2cccc(C(F)(F)F)c2)s1

Procedure:
3-(2,3-Dichloro-4-hydroxyphenyl)-1-(5-(3-(trifluoromethyl)phenyl)thien-2-yl)prop-2-en-1-one is prepared from 1-(5-(3-(trifluoromethyl)phenyl)thien-2-yl)ethanone and 2,3-dichloro-4-hydroxybenzaldehyde according to general procedure B, at 50° C. for 30 hours. The evaporation residue is purified by silica-gel chromatography.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.CN(C=O)C.[CH:14]1([C:17]2[CH:22]=[C:21]([C:23]([O:25][CH3:26])=[O:24])[C:20]([OH:27])=[CH:19][C:18]=2[C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=2[F:35])[CH2:16][CH2:15]1>O>[Cl:1][C:19]1[C:20]([OH:27])=[C:21]([C:23]([O:25][CH3:26])=[O:24])[CH:22]=[C:17]([CH:14]2[CH2:16][CH2:15]2)[C:18]=1[C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=1[F:35]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)c1cc(C2CC2)c(-c2ccc(F)cc2F)cc1O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(C2CC2)c(-c2ccc(F)cc2F)c(Cl)c1O
Reaction time: 3 h
Yield: 91 %

Procedure:
N-Chlorosuccinimide (1.65 g) was added at room temperature to a DMF (40 mL) solution of methyl 2-cyclopropyl-2′,4′-difluoro-5-hydroxybiphenyl-4-carboxylate (3.13 g), and the mixture was stirred at the same temperature as above for 3 hours in a nitrogen atmosphere. Then, N-chlorosuccinimide (0.549 g) was further added thereto, and the mixture was stirred at the same temperature as above for 16 hours in a nitrogen atmosphere. Water was added to the reaction mixture at room temperature, and the mixture was stirred at 0° C. for 1 hour. The deposited crystals were collected by filtration. The obtained crystals were dissolved in ethyl acetate and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure to obtain the title compound (3.17 g).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]#[N:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][O:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[CH2:20][Mg]Cl.CO.[CH2:29]([O:31][CH2:32][CH3:33])C>>[C:10]([OH:17])(=[O:11])[CH3:14].[C:18]([OH:17])(=[O:31])[CH3:26].[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([NH2:15])([CH2:6][C:7]2[CH:2]=[CH:3][CH:4]=[CH:33][C:32]=2[O:31][CH3:29])[CH2:20][C:19]2[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=2[O:17][CH3:16])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccccc1C[Mg]Cl
Reactant: N#CC1CN(Cc2ccccc2)CCO1
Reactant: CCOCC
Solvent: CO
Product: CC(=O)O
Product: COc1ccccc1CC(N)(Cc1ccccc1OC)C1CN(Cc2ccccc2)CCO1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-benzyl-morpholine-2-carbonitrile (10 g, 49.5 mmol) in dry diethyl ether (100 mL) at −10° C. under an atmosphere of nitrogen is added a solution of 2-methoxybenzylmagnesium chloride (0.25M solution in tetrahydrofuran, 218 mL, 54.5 mmol) available from Aldrich Chemical Company or Rieke Metals) and the reaction mixture is further stirred at −10° C. for 30 minutes. Then the reaction is allowed to warm to room temperature and stirred overnight The reaction is then cooled to 0° C. and quenched by addition of hydrochloric acid (5N aqueous solution, 50 mL) and the resulting mixture is stirred for 10 minutes at 0° C. Next the solution is basified with sodium hydroxide (2N aqueous solution), filtered through Celite® then extracted with diethyl ether, the organics collected, dried (MgSO4) and the solvent removed under reduced pressure to give a residue which is taken up into methanol and purified by SCX-2 chromatography prior to silica gel chromatography (eluent, ethyl acetate/n-hexane, 0/100 to 40/60 [v/v]). The fractions containing the correct mass (FIA+[M+H]+=447) are collected and purified via preparative HPLC to give 80 (72 mg). MW 566.69; C28H34N2O3.C4H8O4; LCMS (12 minutes method): m/z)=447.2 [M−C4H8O4+H]+ RT 4.60 min.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[NH2:21][CH:22]([CH:26]1[CH2:28][CH2:27]1)[C:23]([NH2:25])=[O:24].CO>CCCCCCC>[C:23]([CH:22]([NH:21][C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])[CH:26]1[CH2:28][CH2:27]1)(=[O:24])[NH2:25]
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: NC(=O)C(N)C1CC1
Solvent: CO
Solvent: CCCCCCC
Product: NC(=O)C(NC(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)C1CC1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethyloxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 69b) and α-amino-cyclopropaneacetamide (CAN 1100749-41-4) as starting materials. The product was isolated by chiral chromatography on Chiralpak AD using heptane/40% ethanol as eluent. The (+)-enantiomer was isolated. LC-MS (UV peak area/ESI) 100%, 381.1739 (M+H)+, αD20 (MeOH)=+35.0°.