Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[NH:17][C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([O:25][CH:26]2[CH2:31][CH2:30][N:29]([CH:32]([CH3:34])[CH3:33])[CH2:28][CH2:27]2)=[CH:20][CH:19]=3)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)S(O[CH2:41][CH:42]([F:44])[F:43])(=O)=O>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]([C:16]2[N:17]([CH2:41][CH:42]([F:44])[F:43])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([O:25][CH:26]2[CH2:31][CH2:30][N:29]([CH:32]([CH3:34])[CH3:33])[CH2:28][CH2:27]2)=[CH:20][CH:19]=3)=[O:15])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCN(C(=O)OC(C)(C)C)CC4)cc3c2)CC1
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)n3CC(F)F)CC1

Procedure:
The title compound was prepared in analogy to example 40a), from 4-[5-(1-isopropyl-piperidin-4-yloxy)-1H-indole-2-carbonyl]-piperazine-1-carboxylic acid tert-butyl ester and 2,2-difluoroethyl trifluoromethanesulfonate. Off-white solid. MS (m/z): 535.5 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[Cl:15])=[CH:12][C:11]([Br:16])=[CH:10][CH:9]=2)=[O:5])[CH3:2].[CH:17]([O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)([CH3:19])[CH3:18]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([C:24]2[CH:25]=[CH:26][C:21]([O:20][CH:17]([CH3:19])[CH3:18])=[CH:22][CH:23]=2)[C:8]2[C:13]([C:14]=1[Cl:15])=[CH:12][C:11]([Br:16])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CC(C)Oc1ccc(B(O)O)cc1
Reactant: CCOC(=O)c1[nH]c2ccc(Br)cc2c1Cl
Product: CCOC(=O)c1c(Cl)c2cc(Br)ccc2n1-c1ccc(OC(C)C)cc1

Procedure:
The sub-title compound was prepared in accordance with Example 8(c), using 5-bromo-3-chloro-1H-indole-2-carboxylic acid ethyl ester (see step (a) above) and 4-isopropoxyphenylboronic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:15]=1[C:9]1([CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)[N:8]([CH3:16])[C:7]2=[O:17].[Cl:18][C:19]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:20]=1[CH:21]=[CH:22][C:23](O)=[O:24]>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:15]=1[C:9]1([CH2:10][CH2:11][N:12]([C:23](=[O:24])/[CH:22]=[CH:21]/[C:20]3[C:19]([Cl:18])=[CH:29][CH:28]=[CH:27][C:26]=3[Cl:30])[CH2:13][CH2:14]1)[N:8]([CH3:16])[C:7]2=[O:17]
Reactant: O=C(O)C=Cc1c(Cl)cccc1Cl
Reactant: CN1C(=O)c2cccc(Cl)c2C12CCNCC2
Product: CN1C(=O)c2cccc(Cl)c2C12CCN(C(=O)/C=C/c1c(Cl)cccc1Cl)CC2

Procedure:
The title compound was prepared following a procedure analogous to that described in Example 1 using 7-chloro-2-methylspiro[isoindoline-1,4′-piperidin]-3-one and 2,6-dichlorocinnamic acid. 1H NMR (CDCl3) 1.82 (m, 2H), 2.99 (m, 2H), 3.35 (s, 3H), 3.68 (m, 1H), 3.88 (m, 1H), 4.18 (m, 1H), 4.49 (m, 1H), 7.06 (d, 1H), 7.1-7.6 (5H), 7.76 (2H).
Reaction SMILES: C(OC([N:8]1[C:12]2[C:13]([F:25])=[CH:14][C:15]([NH:18]C(NCCN)=S)=[C:16]([CH3:17])[C:11]=2[N:10]=[CH:9]1)=O)(C)(C)C>CO>[F:25][C:13]1[C:12]2[N:8]=[CH:9][NH:10][C:11]=2[C:16]([CH3:17])=[C:15]([NH:18][N:10]2[CH2:11][CH2:12][N:8]=[CH:9]2)[CH:14]=1
Reactant: Cc1c(NC(=S)NCCN)cc(F)c2c1ncn2C(=O)OC(C)(C)C
Solvent: CO
Product: Cc1c(NN2C=NCC2)cc(F)c2nc[nH]c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of N-(1-tert-butoxycarbonyl-7-fluoro-4-methyl-5-benzimidazolyl)-N'-2-aminoethylthio-urea (0.5 g) and mercuric acetate (0.52 g) in methanol (150 mL) is stirred at room temperature for 1 hour. The resulting black mixture is filtered on Celite with methanol wash of the solids. The filtrate is rotary evaporated and the residue filtered through a short pad of silica gel, eluting 25% methanol in chloroform containing 1% of ammonium hydroxide. The product-containing fractions are rotary evaporated, the residue diluted with water (15 mL), filtered through a plug of glass wool and lyophilized to afford 7-fluoro-4-methyl-5-(2-imidazolinylamino)benzimidazole as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]([N:8]1[CH:12]=[C:11]([NH:13][C:14](=[O:20])[CH:15]([NH2:19])[CH2:16][CH2:17][CH3:18])[N:10]=[CH:9]1)([CH3:7])[CH3:6].[F:22][C:23]1[CH:24]=[C:25]([CH2:30][C:31](O)=[O:32])[CH:26]=[C:27]([F:29])[CH:28]=1>>[CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]([N:8]1[CH:12]=[C:11]([NH:13][C:14](=[O:20])[CH:15]([NH:19][C:31](=[O:32])[CH2:30][C:25]2[CH:24]=[C:23]([F:22])[CH:28]=[C:27]([F:29])[CH:26]=2)[CH2:16][CH2:17][CH3:18])[N:10]=[CH:9]1)([CH3:6])[CH3:7]
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Reactant: CCCC(N)C(=O)Nc1cn(C(C)(C)CC(=O)OC)cn1
Product: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(C(C)(C)CC(=O)OC)cn1

Procedure:
3-[4-(2-Amino-pentanoylamino)-imidazol-1-yl]-3-methyl-butyric acid methyl ester was coupled with (3,5-Difluoro-phenyl)-acetic acid to provide the title compound: C13 NMR (100 MHz, CDCl3) 13.9, 19.0, 27.9, 28.1, 35.9, 42.7, 46.8, 51.8, 53.1, 56.3, 102.2, 102.5, 102.7, 105.1, 112.2, 112.3, 112.4, 112.5, 131.3, 137.9, 139.2, 161.8, 164.2, 164.3, 169.4, 169.9, 170.0; MS 451.2 m/z (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].Cl[CH:13](Cl)C.CO.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[CH3:13][O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([OH:11])=[C:2]([OH:1])[CH:3]=1
Reactant: O=C(O)c1ccc(O)c(O)c1
Reactant: CC(Cl)Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(O)c(O)c1

Procedure:
A mixture of 180 g of 3,4-dihydroxybenzoic acid, 360 ml of dichloroethane, 142 ml of methanol and 18 g of p-toluenesulfonic acid was boiled on a water separator, until distillate is clear. The solvent was evaporated, and the residue was admixed with 1.5 liters of diethyl ether, washed with 1 liter of a saturated aqueous sodium bicarbonate solution and twice with each 0.4 liter of aqueous sodium chloride solution. After evaporation again, the residue was recrystallized from 3 liters of toluene to obtain the product. m.p. 136°-137° C.
Reaction SMILES: C[O:2][C:3](=[O:25])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1.[OH-].[Na+:27]>>[Na+:27].[O:18]([C:15]1[CH:14]=[CH:13][C:12]([N:9]2[CH2:10][CH2:11][N:6]([CH2:5][CH2:4][C:3]([O-:25])=[O:2])[CH2:7][CH2:8]2)=[CH:17][CH:16]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COC(=O)CCN1CCN(c2ccc(Oc3ccccc3)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Product: O=C([O-])CCN1CCN(c2ccc(Oc3ccccc3)cc2)CC1
Yield: 97 %

Procedure:
The title compound (98 mg, 97%) was prepared from the compound from step 1 (100 mg, 0.29 mmol) and 1N NaOH (0.29 mL, 0.29 mmol) by the procedure described in Example 2: MS (ESI) m/z 327 (M+H); 1H NMR (400 MHz, CD3OD) δ 2.44 (m, 2H), 2.72 (t, J=4.8 Hz, 4H), 2.78 (t, J=8.0 Hz, 2H), 3.17 (t, J=4.8 Hz, 4H), 6.88-6.92 (m, 4H), 6.97-7.04 (m, 3H), 7.28 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH3:30])[C:8]([CH:19]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([O:22]CC)=[O:21])=[C:9]2[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[C:31]([CH:33]1[CH2:35][CH2:34]1)#[CH:32]>CC#N.O>[C:26]([O:25][CH:19]([C:8]1[C:7]([CH3:30])=[CH:6][C:5]2[C:10](=[CH:11][C:2]([C:32]#[C:31][CH:33]3[CH2:35][CH2:34]3)=[CH:3][CH:4]=2)[C:9]=1[C:12]1[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=1)[C:20]([OH:22])=[O:21])([CH3:28])([CH3:29])[CH3:27]
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)cc2ccc(Br)cc2c1-c1ccc(Cl)cc1
Reactant: C#CC1CC1
Solvent: CC#N
Solvent: O
Product: Cc1cc2ccc(C#CC3CC3)cc2c(-c2ccc(Cl)cc2)c1C(OC(C)(C)C)C(=O)O

Procedure:
2-tert-Butoxy-2-(1-(4-chlorophenyl)-7-(cyclopropylethynyl)-3-methylnaphthalen-2-yl)acetic acid (75) was prepared by the method of Example 67 from ethyl 2-(7-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate using ethynylcyclopropane. 1H-NMR: 400 MHz, (CD3OD) δ: 7.69 (m, 2H), 7.57 (m, 3H), 7.32 (m, 2H), 7.18 (s, 1H), 5.16 (s, 1H), 2.59 (s, 3H), 1.42 (br m, 1H), 0.97 (s, 9H), 0.83 (br m, 2H), 0.68 (br m, 2H). HPLC (Kinetex 2.6u, 50×4.6 mm, 2-100% MeCN/H2O+0.05% HOAc, 5 min run): tR (min)=3.78.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:29])[CH2:9][NH:10][CH:11]([CH3:28])[CH2:12][C:13]2[CH:27]=[CH:26][C:16]3[O:17][C:18]([C:23]([OH:25])=[O:24])([C:20]([OH:22])=[O:21])[O:19][C:15]=3[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:30][Si:31]([CH3:37])([CH3:36])[CH2:32][CH2:33][CH2:34]O.Cl.[K+].[Br-]>C(Cl)(Cl)Cl>[CH3:30][Si:31]([CH3:37])([CH3:36])[CH2:32][CH2:33][CH2:34][O:24][C:23]([C:18]1([C:20]([O:22][CH2:34][CH2:33][CH2:32][Si:31]([CH3:37])([CH3:36])[CH3:30])=[O:21])[O:17][C:16]2[CH:26]=[CH:27][C:13]([CH2:12][CH:11]([NH:10][CH2:9][CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[OH:29])[CH3:28])=[CH:14][C:15]=2[O:19]1)=[O:25]
Reactant: CC(Cc1ccc2c(c1)OC(C(=O)O)(C(=O)O)O2)NCC(O)c1cccc(Cl)c1
Reactant: C[Si](C)(C)CCCO
Agent: Cl
Agent: [Br-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CC(Cc1ccc2c(c1)OC(C(=O)OCCC[Si](C)(C)C)(C(=O)OCCC[Si](C)(C)C)O2)NCC(O)c1cccc(Cl)c1

Procedure:
The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid and 3-trimethylsilylpropanol according to the procedure of Example 30 as a white foam (HCl salt); 1H NMR (CDCl3) δ 0.01 (s, 18H), 0.46 (m, 4H), 1.33 (d, J=6.3 Hz, 3H), 1.70 (m, 4H), 2.80 (m, 1H), 3.18 (m, 2H), 3.46(m 2H), 4.24(t, J=7.0 Hz, 4H), 5.47 (bd, J=9.7 Hz, I H), 5.70 (bs, 1H), 6.80 (m, 3H), 7.25 (m, 2H), 7.43 (s, 1H), 8.70 (bs, 1H), 10.10 (bs, 1H); IR (KBr): 1765 cm-1 (C=O); MS (ES) m/z 650 (MH+); [α]D25 -22° (c, 1.0, CHCl3). Anal. Calcd. for C32H48ClNO7Si2 ·HCl: C, 55.96; H, 7.04; N, 2.04 Cl, 10.32; Si, 8.18. Found: C, 55.82; H, 7.21; N, 1.87; Cl, 10.22; Si, 7.76.
Reaction SMILES: [CH2:1]([C@@H:3]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][C:12]([C:14]([O:16][CH3:17])=[O:15])=[CH:13][C:5]=2[O:4]1)[CH3:2].[H-].[Na+].[CH2:20](I)[CH3:21].O>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([C@@H:3]1[C:8](=[O:9])[N:7]([CH2:20][CH3:21])[C:6]2[CH:10]=[CH:11][C:12]([C:14]([O:16][CH3:17])=[O:15])=[CH:13][C:5]=2[O:4]1)[CH3:2]
Reactant: CC[C@H]1Oc2cc(C(=O)OC)ccc2NC1=O
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC[C@H]1Oc2cc(C(=O)OC)ccc2N(CC)C1=O
Temperature: 25 °C
Yield: 89.3 %

Procedure:
To a solution of (R)-2-ethyl-7-methoxycarbonyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine [prepared in Preparation 15(2)] (2.00 g) in dimethylformamide (20 ml) were added 60% sodium hydride (in oil) (0.35 g) and ethyl iodide (1.46 g) and the mixture was stirred at room temperature for two and a half hours. Water was added to the reaction solution and extraction with ethyl acetate was conducted. The solvent was distilled off under reduced pressure and the resulting residue was subjected to purification by column chromatography using ethyl acetate/hexane [1:4 (v/v)] to give (R)-2,4-diethyl-7-methoxycarbonyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine(2.0g).
Reaction SMILES: C(OC([NH:6][C:7]([NH2:9])=S)=O)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([NH2:18])=[N:16][CH:17]=1.Cl.NO.CCN(C(C)C)C(C)C>C(O)C.CO>[CH3:10][O:11][C:12]1[CH:13]=[CH:14][C:15]2[N:16]([N:6]=[C:7]([NH2:9])[N:18]=2)[CH:17]=1
Reactant: COc1ccc(N)nc1
Reactant: CCOC(=O)NC(N)=S
Agent: Cl
Agent: NO
Solvent: CCO
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2nc(N)nn2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
To 5-methoxypyridin-2-amine ethoxycarbonyl thiourea (10.21 g, 40 mmol) in ethanol (57 mL) and methanol (57 mL) was added hydroxylamine hydrochloride (14 g, 200 mmol) and Hunig's Base (21 mL, 120 mmol). The mixture was stirred at room temperature for 2 hours, and then heated at 60° C. for 4 hours. The reaction was cooled to room temperature and filtered to remove solids. It was concentrated in vacuo and then suspended in chloroform. The solids were filtered off to yield 6-methoxy-[1,2,4]triazolo[1,5-a]pyridin-2-amine (6.05 g, 33.2 mmol, 83% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 8.30 (1H, d, J=1.83 Hz), 7.24-7.32 (1H, m), 7.16-7.23 (1H, m), 5.82 (2H, br. s.), 3.78 (3H, s). MS (LC/MS) R.T.=0.53; [M+H]+=165.2.
Reaction SMILES: [CH2:1]([NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH:21]=O)=[CH:17][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].C(O)(=O)C.[F:28][C:29]([F:38])([F:37])[C:30]1[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[CH2:1]([NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][NH:36][C:33]2[CH:34]=[CH:35][C:30]([C:29]([F:28])([F:37])[F:38])=[CH:31][CH:32]=2)=[CH:17][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]
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: CCCCCCCCCCCCNC(=O)c1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCCCCCCCCCCCNC(=O)c1ccc(CNc2ccc(C(F)(F)F)cc2)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
To a solution of N-dodecyl-4-formyl-benzamide (Example 10, step a) (1.00 g, 3.115 mmol), acetic acid (0.227 g, 3.78 mmol) and 4-trifluoromethyl-phenylamine (0.609 g, 3.78 mmol) in DCE (25 mL) was added at once NaBH(OAc)3 (0.801 g, 3.78 mmol). The resulting mixture was stirred overnight at 70° C. A saturated solution of NaHCO3 (10 mL) was added to the reaction mixture, the aqueous layer was separated and extracted with DCM (3×50 mL). The combined organic layers were dried over MgSO4, filtered and concentrated to give a colorless oil. This crude product was purified by column chromatography over silica gel (4/1 c-Hex/AcOEt to 3/1 in about 0.5 h) to give the title compound as a colorless oil (0.824 g, 63%). 1H NMR (CD3OD, 300 MHz) δ 7.74 (d, 2H, J=8.3 Hz), 7.43 (d, 2H, J=8.3 Hz), 7.29 (d, 2H, J=8.7 Hz), 6.63 (d, 2H, J=8.3 Hz), 4.42 (s, 2H), 3.35 (m, 2H), 1.58 (m, 2H), 1.27 (m, 18H), 0.88 (m, 3H). M+(LC/MS(ESI)): 463.0; M−(LC/MS(ESI)): 461.3. HPLC (Condition A), Rt: 6.84 min (HPLC purity: 98.5%).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:3].[C:21]([CH2:24][C:25](=[O:27])[CH3:26])(=[O:23])[CH3:22].C(N(CC)CC)C>C(OCC)C>[CH2:5]([O:4][C:2]([O:27][C:25]([CH3:26])=[CH:24][C:21](=[O:23])[CH3:22])=[O:3])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CC(=O)CC(C)=O
Reactant: CCCCCCCCCCCCCCCCOC(=O)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCOC(=O)OC(C)=CC(C)=O
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
30.4 g (0.1 mole) of n-hexadecyl chloroformate, 15 g (0.15 mole) of acetylacetone and 80 ml of diethyl ether are charged to a 250 ml flask. Then a solution of 11 g (0.11 mole) of triethylamine in 20 ml of diethyl ether is added, with stirring, at a temperature below 10° C. over 25 minutes. The mixture is warmed to room temperature and allowed to stand for 2 days. The precipitate is isolated by filtration and washed with diethyl ether. The residue is triethylamine hydrochloride (13.8 g; theory: 13.8 g). The filtrate is washed twice with water and then dried over Na2SO4. First the solution is concentrated by rotary evaporation and then the residual acetylacetone and the dietyl ether are distilled off with an oil pump, to give colourless crystals with a melting point of 33°-35° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([O:13][CH3:14])[C:10]([OH:12])=[O:11])=[CH:4][C:3]=1[O:15][CH3:16].[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18].N1C=CN=C1.O>C(Cl)Cl.CN(C=O)C>[C:20]([Si:17]([CH3:19])([CH3:18])[O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([O:13][CH3:14])[C:10]([OH:12])=[O:11])=[CH:4][C:3]=1[O:15][CH3:16])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1cc(CC(OC)C(=O)O)ccc1O
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(CC(OC)C(=O)O)ccc1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-(4-hydroxy-3-methoxy-phenyl)-2-methoxy-propionic acid (1.02 g, 4.87 mmol) in CH2Cl2-DMF (20 mL=10:1) was added tert-butyl-dimethylsilyl chloride (1.75 g, 11.68 mmol) and imidazole (0.70 g, 10.24 mmol). The resulting solution was stirred at room temperature overnight. Water (15 mL) was added, and the aqueous phase was extracted with hexanes (30 mL). The hexanes layer was washed with water (10 mL), dried (MgSO4), filtered, and concentrated. The crude product was dissolved in ethyl acetate (10 mL), and a saturated solution of K2CO3 (5 mL) was added. The resulting mixture was stirred for 2 hours at room temperature. The aqueous layer was extracted with ethyl acetate (10 mL), acidified to pH 3, and extracted again with ethyl acetate (3×10 mL). The later organic layers were combined and washed with brine (20 mL), dried (MgSO4), and concentrated to a yellow oil (1.2 g, 77%). 1H-NMR (200.15 MHz, CDCl3): δ 6.78–6.67 (m, 3H), 3.96 (dd, 1H, J=7.8, 4.0), 3.78 (s, 3H), 3.35 (s, 3H), 3.09 (dd, 1H, J=14.2, 4.0), 2.91 (dd, 1H, J=14.2, 7.8), 0.98 (s, 9H), 0.13 (6H, s).
Reaction SMILES: ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.COC1C=CC(C[O:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]2[O:29][C:30]2[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[C:32]([C:38]([F:41])([F:40])[F:39])[CH:31]=2)=CC=1.C(Cl)Cl.O>CC(=O)OCC>[OH:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]1[O:29][C:30]1[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[C:32]([C:38]([F:39])([F:40])[F:41])[CH:31]=1
Reactant: COc1ccc(COC2CCCCC2Oc2ccc(C#N)c(C(F)(F)F)c2)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: N#Cc1ccc(OC2CCCCC2O)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 72 h
Yield: 32 %

Procedure:
2,3,-Dichloro-5,6-dicyano-1,4-benzoquinone (hereinafter “DDQ) (18.2 g, 80.2 mmol) was added to a solution of 4-[2-(4-methoxy-benzyloxy)cyclohexyloxy]-2-trifluoromethyl-benzonitrile (17.77 g, 43.83 mmol), methylene chloride (500 mL) and water (50 mL). The reaction was allowed to stir at room temperature for 3 days. A solid formed and was filtered off. The resulting filtrate was passed through a silica plug and condensed under reduced pressure. A column was run using a gradient of 17-80% EA in Hexanes. A second column was run using 4:1 Hex:EA. This yielded the desired product, 4-(2-hydroxy-cyclohexyloxy)-2-trifluoromethyl-benzonitrile (4.0 g, 32% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][CH2:14][CH2:15][C:16]([OH:18])=O)(=[O:12])=[O:11])([O-:3])=[O:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>O1CCCC1>[CH3:31][N:32]1[CH2:37][CH2:36][N:35]([C:16](=[O:18])[CH2:15][CH2:14][NH:13][S:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])(=[O:11])=[O:12])[CH2:34][CH2:33]1
Reactant: O=C(O)CCNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: CN1CCNCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CN1CCN(C(=O)CCNS(=O)(=O)c2ccccc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.9 %

Procedure:
To a solution of methyl 3-(2-nitrobenzenesulfonylamino)propionate (6.15 g) in ethanol (20 mL)-methanol (5 mL) was added 5 mol/L aqueous sodium hydroxide solution (20 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was acidified by addition of 2 mol/L hydrochloric acid (55 mL), and the resulting mixture was extracted with ethylacetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was treated with n-hexane and ethylacetate. The precipitated crystals were collected by filtration, washed with n-hexane and dried under reduced pressure to give 3-(2-nitrobenzenesulfonylamino)propionic acid (5.83 g). To a solution of the obtained 3-(2-nitrobenzenesulfonylamino)propionic acid (0.5 g) in tetrahydrofuran (5 mL) was added 1,1′-carbonylbis-1H-imidazole (0.35 g), and the mixture was stirred at room temperature for 2 hours. To the reaction mixture was added 1-methylpiperazine (0.46 g), and the mixture was stirred at 50° C. for 3 days. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on aminopropylated silica gel (eluent: dichloromethane/methanol 40/1) to give the title compound (0.61 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][CH2:12][N:7]3[C@H:6]3[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C@@H:5]23)[CH:10]=1.[F:24][C:25]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=1B(O)O>>[F:24][C:25]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=1[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][CH2:12][N:7]3[C@H:6]3[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:22])([CH3:23])[CH3:21])=[O:18])[CH2:16][C@@H:5]23)[CH:10]=1
Reactant: COc1ccc(B(O)O)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(Br)cc3c1N2CC3
Product: COc1ccc(-c2cc3c4c(c2)[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2N4CC3)c(F)c1
Yield: 54.7 %

Procedure:
Tert-butyl (6aS,10aR)-2-(2-fluoro-4-methoxyphenyl)-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate (116 mg, 55%) was prepared by the method of Example 89 step C from tert-butyl (6aS,10aR)-2-bromo-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate (189 mg, 0.5 mmol) and 2-fluoro-4-methoxyphenylboronic acid (158 mg, 1.0 mmol).
Reaction SMILES: I.I.[N:3]1([C:10]2[N:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:13]3[CH:20]=[CH:21][CH:22]=[CH:23][C:12]=3[N:11]=2)[CH2:9][CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH:36]=[N:35][N:34]=[N:33]2)=[CH:28][C:27]=1[C:37]([N:39]1[CH2:43][CH2:42][C@:41]([CH2:50][CH2:51]OS(C)(=O)=O)([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:40]1)=[O:38].C(N(C(C)C)CC)(C)C>C(#N)C>[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH:36]=[N:35][N:34]=[N:33]2)=[CH:28][C:27]=1[C:37]([N:39]1[CH2:43][CH2:42][C@:41]([CH2:50][CH2:51][N:6]2[CH2:7][CH2:8][CH2:9][N:3]([C:10]3[N:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:13]4[CH:20]=[CH:21][CH:22]=[CH:23][C:12]=4[N:11]=3)[CH2:4][CH2:5]2)([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:40]1)=[O:38]
Reactant: COc1ccc(-n2cnnn2)cc1C(=O)N1CC[C@](CCOS(C)(=O)=O)(c2ccccc2)C1
Reactant: CCCCCn1c(N2CCCNCC2)nc2ccccc21
Agent: I
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCCCCn1c(N2CCCN(CC[C@]3(c4ccccc4)CCN(C(=O)c4cc(-n5cnnn5)ccc4OC)C3)CC2)nc2ccccc21
Yield: 19 %

Procedure:
Heat a mixture of 2-[1,4]diazepan-1-yl-1-pentyl-1H-benzoimidazole dihydroiodide (0.83 g, 1.53 mmol), methanesulfonic acid 2-{(S)-1-[1-(2-methoxy-5-tetrazol-1-yl-phenyl)-methanoyl]-3-phenyl-pyrrolidin-3-yl}-ethyl ester (0.713 g, 1.51 mmol, example 47.2), diisopropylethylamine (1 mL, 5.74 mmol) and acetonitrile (15 mL) at 90° C. for 72 hours. Concentrate to dryness and dissolve the residue in dichloromethane. Wash the dichloromethane phase with NaHCO3 (10%, 10 mL) and brine (four 10 mL portions), dry (Na2SO4) the organic phase, filter and evaporate. Purify the residue by silica gel chromatography (3.5×35 cm) eluting with 95:5:0.05 dichloromethane:methanol:30% ammonium hydroxide solution. Concentrate the desired fractions to afford 0.19 g of the title compound, Rf=0.80 (silica gel, 90:10:0.1 dichloromethane:methanol:30% ammonium hydroxide solution). The product may be converted to the dihydrochloride by methods as are well known in the art.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=3[O:24][CH3:25])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:28]1[N:33]=[CH:32][CH:31]=[CH:30][N:29]=1>>[F:23][C:21]1[CH:20]=[CH:19][C:18]([O:24][CH3:25])=[C:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:28]4[N:33]=[CH:32][CH:31]=[CH:30][N:29]=4)=[O:5])[N:7]=[CH:8]3)[CH:12]=2)[CH:22]=1
Reactant: Brc1ncccn1
Reactant: COc1ccc(F)cc1-c1cccc(-n2cnc(C(=O)N(C)OC)c2)c1
Product: COc1ccc(F)cc1-c1cccc(-n2cnc(C(=O)c3ncccn3)c2)c1

Procedure:
This compound was prepared by method C using compound 12b and 2-bromopyrimidine. HRMS (ESI+): m/z=375.1249 [M+H]