Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=3[N:16]=[C:15]2[CH:25]([F:27])[F:26])[N:3]=1.[NH:28]1[CH2:33][CH2:32][CH:31]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:30][CH2:29]1.CCN(C(C)C)C(C)C>C1COCC1>[F:26][CH:25]([F:27])[C:15]1[N:14]([C:4]2[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=[C:2]([N:28]3[CH2:29][CH2:30][CH:31]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:39])([CH3:38])[CH3:40])[CH2:32][CH2:33]3)[N:3]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=2[N:16]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(Cl)nc(N2CCOCC2)n1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CCC(NC(=O)OC(C)(C)C)CC2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.5 %

Procedure:
A mixture of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole (0.992 g, 2.5 mmol), tert-butyl 4-piperidinylcarbamate (1.00 g, 5 mmol), and DIPEA (0.65 g, 5 mmol) in THF (100 mL) was stirred at room temperature for 30 min. The solution was then concentrated and diluted with water (100 mL) containing 1 mL of acetic acid. The resulting solid was collected, washed with water, and dried to give 1.38 g (98%) of tert-butyl 1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-piperidinylcarbamate: mp (MeOH) 208-209° C.; 1H NMR (CDCl3) δ 7.88 (d, J=8.1 Hz, 1H), 7.48 (t, JHF=53.6 Hz, 1H), 7.34 (t, J=8.2 Hz, 1H), 6.81 (d, J=7.9 Hz, 1H), 4.66 (br d, J=13.4 Hz, 2H), 4.46 (m, exchangeable with D2O, 1H), 4.04 (s, 3H), 3.87 (m, 4H), 3.78 (m, 5H), 3.12 (m, 2H), 2.07 (br d, J=14.0 Hz, 2H), 1.46 (s, 9H), 1.45-1.33 (m, 2H); Anal. Calcd. for C26H34F2N8O4: C, 55.7; H, 6.1; N, 20.0. Found: C, 55.85; H, 6.1; N, 20.1%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[S:13][C:12]([C:14]([O:16][CH3:17])=[O:15])=[CH:11][C:10]=1[C:18]1[CH:23]=[CH:22][C:21]([O:24]C)=[CH:20][CH:19]=1.B(Br)(Br)Br.CO>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[S:13][C:12]([C:14]([O:16][CH3:17])=[O:15])=[CH:11][C:10]=1[C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1
Reactant: COC(=O)c1cc(-c2ccc(OC)cc2)c(-c2ccc(F)cc2Cl)s1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1cc(-c2ccc(O)cc2)c(-c2ccc(F)cc2Cl)s1

Procedure:
The compound obtained in stage 16D) is added to 100 ml of CH2Cl2, cooling is carried out to −50° C. and 40 ml of a 1M solution of BBr3 in CH2Cl2 are added. The temperature is allowed to return to 20° C. and then 20 ml of methanol are added. The mixture is concentrated to dryness and the residue is taken up in CH2Cl2, washed with water, MgSO4 and concentrated to dryness. After purifying by chromatography on silica (heptane up to heptane/AcOEt 75/25), 4.8 g of the expected compound are obtained.
Reaction SMILES: I[CH2:2][Si:3]([CH3:11])([CH3:10])[O:4][Si:5]([CH2:8]I)([CH3:7])[CH3:6].[NH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.C1(C)C=CC=CC=1>O>[N:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH2:13][N:12]1[CH2:8][Si:5]([CH3:6])([CH3:7])[O:4][Si:3]([CH3:11])([CH3:10])[CH2:2]1
Reactant: C[Si](C)(CI)O[Si](C)(C)CI
Reactant: NCc1ccccn1
Solvent: Cc1ccccc1
Solvent: O
Product: C[Si]1(C)CN(Cc2ccccn2)C[Si](C)(C)O1
Reaction time: 24 h

Procedure:
To 41.4 g. (0.1 mole) of 1,3-bis-iodomethyl-1,1,3,3-tetramethyl-disiloxane there is added dropwise with stirring 32.4 g. (0.3 mole) of 2-aminomethyl-pyridine while maintaining the temperature at 20° C. Stirring is continued at room temperature for 24 hours. The now heterogeneous mixture is combined with approximately 0.5 l. of toluene followed by approximately 0.5 l. of water. The equilibrated aqueous phase is then extracted with two 100 ml. portions of toluene. The combined organic phase is then washed twice with approximately 100 ml. of water to give 4-(2-pyridylmethyl)-2,2,6,6-tetramethyl-1-oxa-4-aza-2,6-disilacyclohexane as the crude free base.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([CH:10]([OH:12])[CH3:11])[C:7]([C:13]([F:16])([F:15])[F:14])=[CH:6][C:5]=1[NH:17]C(=O)C.O.[C:23]1(C)[CH:28]=CC(S(O)(=O)=O)=C[CH:24]=1>CC(O)C>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([CH:10]([O:12][CH:23]([CH3:28])[CH3:24])[CH3:11])[C:7]([C:13]([F:14])([F:15])[F:16])=[CH:6][C:5]=1[NH2:17]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COC(=O)c1cc(C(C)O)c(C(F)(F)F)cc1NC(C)=O
Solvent: O
Solvent: CC(C)O
Product: COC(=O)c1cc(C(C)OC(C)C)c(C(F)(F)F)cc1N
Temperature: 80 °C
Reaction time: 18 h
Yield: 43.7 %

Procedure:
A solution of 2-acetylamino-5-(1-hydroxy-ethyl)-4-trifluoromethyl-benzoic acid methyl ester (500 mg, 1.64 mmol) in i-PrOH (5 mL) was treated by addition of p-toluenesulfonic acid monohydrate (99.9 mg, 0.517 mmol) and stirred at 80° C. for 18 h. The reaction mixture was cooled then concentrated in vacuo. The residue was purified by column chromatography (silica gel, 5:1 hexanes/EtOAc) to give title product (69 mg, 14% yield) as colorless crystals. m.p.: 87-90° C., API-ES: m/z 306 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH3:20]O>CC(OC)(C)C>[CH3:20][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])=[CH:10][C:2]=1[NH2:1]
Reactant: CCCCOc1ccc(C(=O)O)c(N)c1
Reactant: CO
Solvent: O=S(Cl)Cl
Solvent: COC(C)(C)C
Product: CCCCOc1ccc(C(=O)OC)c(N)c1

Procedure:
A mixture of 2-amino-4-butoxybenzoic acid (2.0 g), thionyl chloride (1.2 g) and methanol (33 mL) was boiled under reflux for 24 hours. The reaction solution was diluted with MTBE and washed with sodium hydroxide solution. The organic phase was dried and concentrated. The product with the molecular weight of 223.27 (C12H17NO3) was obtained in this way; MS (ESI): 224 (M+H+).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([C@H:10]([CH:14]2[CH2:17][NH:16][CH2:15]2)[CH:11]([CH3:13])[CH3:12])[CH:6]=[C:7]([F:9])[CH:8]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH:25]([C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=1)[C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[C:29]#[N:30]>C(#N)C>[Cl:40][C:37]1[CH:36]=[CH:35][C:34]([C@H:25]([N:16]2[CH2:15][CH:14]([C@@H:10]([C:5]3[CH:6]=[C:7]([F:9])[CH:8]=[C:3]([F:2])[CH:4]=3)[CH:11]([CH3:13])[CH3:12])[CH2:17]2)[C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=2)[C:29]#[N:30])=[CH:39][CH:38]=1
Reactant: N#Cc1cccc(C(Br)c2ccc(Cl)cc2)c1
Reactant: CC(C)[C@H](c1cc(F)cc(F)c1)C1CNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)[C@H](c1cc(F)cc(F)c1)C1CN([C@@H](c2ccc(Cl)cc2)c2cccc(C#N)c2)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 106 mg (0.5 mmole) of 3-[(1S)-1-(3,5-difluorophenyl)-2-methylpropyl]azetidine hydrochloride from Step 3 and 0.650 g (2 mmole) of Cs2CO3 in 5 mL dry acetonitrile was stirred at rt in a flask fitted with a small Dean-Stark trap. After 15 minutes, 0.306 g (1 mmole) of 3-[bromo(4-chlorophenyl)methyl]benzonitrile was added and the mixture was heated at 60° C. After 18 h, the solution was partitioned between ethyl acetate and water. The layers were separated and the organic layer was dried over Na2SO4. The solution was filtered and the filtrate was concentrated to an oil. The residue was purified by chromatography on a Chiralpak-AD column using 4% isopropanol-heptane to afford two enantiomers. Fractions containing the slower product diastereomer were pooled and concentrated to afford the title compound; Mass Spectrum: m/e=451 (M+1, 35Cl) and 453 (M+1, 37Cl).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.Cl[CH2:40][C:41]1[N:42]2[CH2:48][CH2:47][N:46]=[C:43]2[S:44][CH:45]=1>>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([CH2:23][C:24]1[CH:25]=[N:26][N:27]([CH2:40][C:41]2[N:42]3[CH2:48][CH2:47][N:46]=[C:43]3[S:44][CH:45]=2)[CH:28]=1)[C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Reactant: ClCC1=CSC2=NCCN12
Agent: Cl
Product: CC(C)c1ccc(N(Cc2cnn(CC3=CSC4=NCCN34)c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Yield: 106.8 %

Procedure:
By the reaction and treatment in the same manner as in Example 83 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.72 g) and 3-chloromethyl-5,6-dihydroimidazo[2,1-b]thiazole hydrochloride (0.38 g) as starting materials, 5-benzyloxy-N-({1-[(5,6-dihydroimidazo[2,1-b]thiazol-3-yl)methyl]pyrazol-4-yl}methyl)-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.92 g) was obtained. By the reaction and treatment of this compound in the same manner as in Example 139, N-({1-[(5,6-dihydroimidazo[2,1-b]thiazol-3-yl)methyl]pyrazol-4-yl}methyl)-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide dihydrochloride (0.50 g) was obtained.
Reaction SMILES: [NH:1]([C:8]1([C:14]([OH:16])=[O:15])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na].[OH-].[Na+].Cl[C:21]([O:23][CH2:24][CH3:25])=[O:22]>O1CCCC1>[NH:1]([C:8]1([C:14]([OH:16])=[O:15])[CH2:9][CH2:10][N:11]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C1(Nc2ccccc2)CCNCC1
Reactant: CCOC(=O)Cl
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOC(=O)N1CCC(Nc2ccccc2)(C(=O)O)CC1
Reaction time: 3 h

Procedure:
To a stirred and cooled (ice-salt bath) mixture of 12.1 parts of 4-anilinoisonipecotic acid, sodium salt, 200 parts of sodium hydroxide solution 1N and 20 parts of tetrahydrofuran are added dropwise 6.45 parts of ethyl chloroformate in 25 parts of tetrahydrofuran over 15 minutes and at a temperature between 2° and 5° C. Upon completion, stirring is continued for 3 hours in the cool-bath. The whole is extracted with ether. The aqueous phase is separated and degassed on a rotavapor without heating. The mixture is acidified with glacial acetic acid, whereupon an oil is separated. The latter is stirred in fresh water and extracted with chloroform. The extract is washed three times with water, dried, filtered and evaporated. The residue is crystallized from a mixture of ethyl acetate and petroleumether, yielding 4-anilino-1-(ethoxycarbonyl)isonipecotic acid; mp. 149°-156° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]([B:7]2[O:11][C:10]([CH3:13])([CH3:12])[C:9]([CH3:15])([CH3:14])[O:8]2)=[CH:5][NH:4][N:3]=1.[C:16]([CH:18]=[C:19]1[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20]1)#[N:17].N12CCCN=C1CCCCC2>C(#N)C>[C:16]([CH2:18][C:19]1([N:4]2[CH:5]=[C:6]([B:7]3[O:11][C:10]([CH3:13])([CH3:12])[C:9]([CH3:15])([CH3:14])[O:8]3)[C:2]([CH3:1])=[N:3]2)[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20]1)#[N:17]
Reactant: CC(C)(C)OC(=O)N1CC(=CC#N)C1
Reactant: Cc1n[nH]cc1B1OC(C)(C)C(C)(C)O1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: Cc1nn(C2(CC#N)CN(C(=O)OC(C)(C)C)C2)cc1B1OC(C)(C)C(C)(C)O1
Temperature: 60 °C

Procedure:
A mixture of 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.06 g, 5.10 mmol), tert-butyl 3-(cyanomethylene)azetidine-1-carboxylate (1.00 g, 5.15 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.38 mL, 2.6 mmol) in acetonitrile (20 mL) was heated at 60° C. for 2 h. After cooling, the solvent was removed under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluting with ethyl acetate in hexanes (0-60%) to afford the desired product. LCMS cacld. for C16H24BN4O4 (M−55)+: m/z=347.2. Found: 347.1.
Reaction SMILES: [CH3:1][N:2](/[CH:4]=[C:5]1/[C:6](=O)[CH2:7][N:8]([C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9]/1)C.[CH3:30][C:31]1[CH:35]=C(N)[NH:33][N:32]=1.CC1C=C2N=C3CN(C(OC(C)(C)C)=O)CC3=CN2N=1>C(O)C>[CH3:35][C:31]1[CH:30]=[C:1]2[N:2]=[CH:4][C:5]3[CH2:9][N:8]([C:10]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:7][C:6]=3[N:33]2[N:32]=1
Reactant: Cc1cc(N)[nH]n1
Reactant: CN(C)/C=C1\CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1=O
Agent: Cc1cc2nc3c(cn2n1)CN(C(=O)OC(C)(C)C)C3
Solvent: CCO
Product: Cc1cc2ncc3c(n2n1)CN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C3
Temperature: 25 °C

Procedure:
To a solution of 383 mg (1 mmol) of (4E)-4-[(dimethylamino)methylene]-1-tritylpyrrolidin-3-one in anhydrous ethanol (3 mL) was added 116 mg (1.2 mmol) of 3-methyl-1H-pyrazol-5-amine and the reaction mixture refluxed for 48 h. The mixture was cooled to ambient temperature and the solvent evaporated in vacuo to afford a 10:1 mixture of the title compound and tert-butyl 2-methyl-5H-pyrazolo[1,5-a]pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate. The resulting regioisomers were chromatographed on a Biotage Horizon® system (silica gel, 2 to 3% methanol/methylene chloride gradient) to yield the title compound and its regioisomer as tan solids. LC/MS 417.1 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH3:49])[CH2:3][CH2:4][NH:5][CH2:6][C@:7]12[CH2:45][CH2:44][C@@H:43]([C:46]([CH3:48])=[CH2:47])[C@@H:8]1[C@@H:9]1[C@@:22]([CH3:25])([CH2:23][CH2:24]2)[C@@:21]2([CH3:26])[C@@H:12]([C@:13]3([CH3:42])[C@@H:18]([CH2:19][CH2:20]2)[C:17]([CH3:28])([CH3:27])[C:16]([C:29]2[CH:41]=[CH:40][C:32]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[CH:31][CH:30]=2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1.CCN(C(C)C)C(C)C.[C:59]([CH2:64][CH2:65][C:66](Cl)=[O:67])([O:61][CH2:62]C)=[O:60]>ClCCCl.CN(C1C=CN=CC=1)C>[CH3:49][N:2]([CH3:1])[CH2:3][CH2:4][N:5]([CH2:6][C@:7]12[CH2:45][CH2:44][C@@H:43]([C:46]([CH3:48])=[CH2:47])[C@@H:8]1[C@@H:9]1[C@@:22]([CH3:25])([CH2:23][CH2:24]2)[C@@:21]2([CH3:26])[C@@H:12]([C@:13]3([CH3:42])[C@@H:18]([CH2:19][CH2:20]2)[C:17]([CH3:28])([CH3:27])[C:16]([C:29]2[CH:41]=[CH:40][C:32]([C:33]([O:35][C:36]([CH3:37])([CH3:38])[CH3:39])=[O:34])=[CH:31][CH:30]=2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[C:66](=[O:67])[CH2:65][CH2:64][C:59]([O:61][CH3:62])=[O:60]
Reactant: CCOC(=O)CCC(=O)Cl
Reactant: C=C(C)[C@@H]1CC[C@]2(CNCCN(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=C(C)[C@@H]1CC[C@]2(CN(CCN(C)C)C(=O)CCC(=O)OC)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 5 h
Yield: 70.8 %

Procedure:
To a solution of tert-butyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(dimethylamino)ethylamino)methyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (48 mg, 0.072 mmol) in DCE (2 ml) was added Hunig's base (0.037 ml, 0.215 mmol), 3-carboethoxypropionyl chloride (21.54 mg, 0.143 mmol), and DMAP (1 mg, 8.19 mmol). The mixture was stirred at rt for 5 h then was loaded directly onto a silica gel column and was purified using a 0-5% MeOH in dichloromethane gradient to afford tert-butyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((N-(2-(dimethylamino)ethyl)-4-methoxy-4-oxobutanamido)methyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate as a white foam (53.8 mg, 0.051 mmol, 71.8% yield). LCMS: m/e 785.6 (M+H)+, 3.21 min (method 6).
Reaction SMILES: [CH:1]1[CH2:5][CH:4]=[CH:3][CH:2]=1.[OH:6][CH:7]1[O:11][C:10](=[O:12])[CH:9]=[CH:8]1.C1(C=CC(O)=CC=1)O>C(Cl)(Cl)Cl>[OH:12][CH:10]1[CH:9]2[CH:8]([C:5]3[CH2:4][C:3]2=[CH:2][CH:1]=3)[C:7](=[O:6])[O:11]1
Reactant: O=C1C=CC(O)O1
Reactant: C1=CCC=C1
Agent: Oc1ccc(O)cc1
Solvent: ClC(Cl)Cl
Product: O=C1OC(O)C2C3=CC=C(C3)C12
Temperature: 20 °C
Reaction time: 17 h

Procedure:
244 ml of cyclopentadiene were slowly added to a mixture of 208 g of 5-hydroxy-2(5H)-furanone, 350 mg of hydroquinone and 1.05 liters of chloroform while keeping the temperature at 45°-47° C. and the mixture was stirred at 20° C. for 17 hours and was evaporated to dryness under reduced pressure. The residue was added to isopropyl ether and the mixture was heated to reflux with stirring and was cooled and vacuum filtered. The solid was dissolved in methylene chloride and the solution was treated with activated carbon and evaporated to dryness under reduced pressure. The residue and isopropyl ether was heated to reflux with stirring and was cooled and vacuum filtered to obtain 325.7 g of racemic 1-hydroxy-3-oxo-1,3,3a,7a-tetrahydro-4,7-methano-isobenzofuran melting at 105° C.
Reaction SMILES: [CH:1]([C:3]1[C:8]([C:9]([CH3:11])=[CH2:10])=[CH:7][C:6]([C:12]([F:15])([F:14])[F:13])=[CH:5][C:4]=1[C:16]1[CH:17]=[CH:18][C:19]([C:22]([NH:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:23])=[N:20][CH:21]=1)=[O:2]>C1COCC1.CO>[OH:2][CH2:1][C:3]1[C:8]([CH:9]([CH3:11])[CH3:10])=[CH:7][C:6]([C:12]([F:14])([F:13])[F:15])=[CH:5][C:4]=1[C:16]1[CH:17]=[CH:18][C:19]([C:22]([NH:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:23])=[N:20][CH:21]=1
Reactant: C=C(C)c1cc(C(F)(F)F)cc(-c2ccc(C(=O)NCCC(=O)OCC)nc2)c1C=O
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)CCNC(=O)c1ccc(-c2cc(C(F)(F)F)cc(C(C)C)c2CO)cn1

Procedure:
A solution of ethyl 3-(5-(2-formyl-3-(prop-1-en-2-yl)-5-(trifluoromethyl)phenyl)picolinamido)propanoate (150.1 mg, 0.35 mmol) in THF (5 mL) and MeOH (25 mL) was hydrogenated substituting H-Cube (10 Bar H2) at 40° C. at a flow rate of 1 mL/min. The resulting solution was concentrated to yield the title compound.
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:41]=[CH:40][C:25]([O:26][C:27]2[CH:28]=[C:29]([CH:37]=[CH:38][CH:39]=2)[O:30][CH2:31][CH2:32][CH2:33][C:34](O)=[O:35])=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br.[NH2:43][CH:44]1[CH2:49][CH2:48][O:47][C:45]1=[O:46]>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:26][C:27]2[CH:28]=[C:29]([CH:37]=[CH:38][CH:39]=2)[O:30][CH2:31][CH2:32][CH2:33][C:34]([NH:43][CH:44]2[CH2:49][CH2:48][O:47][C:45]2=[O:46])=[O:35])=[CH:40][CH:41]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[C:10]=1[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2cccc(OCCCC(=O)O)c2)cc1
Reactant: NC1CCOC1=O
Agent: Br
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2cccc(OCCCC(=O)NC3CCOC3=O)c2)cc1

Procedure:
The product from Example 116B (57 mg, 0.10 mmole) and (α-Amino-γ-butyrolactone hydrobromide (36 mg, 0.20 mmole) were processed as in Example 279A to provide the titled compound. 1H NMR (500 M/z, DMSO-d6) δ8.95 (s, 1 H), 8.36 (d, 1 H), 7.23 (m, 8 H), 7.04 (m, 1 H), 6.94 (m, 4 H), 6.69 (dd, 1 H), 6.50 (m, 2 H), 4.53 (d, 1 H), 4.33 (d, 1 H), 4.19 (ddd, 1 H), 4.06 (s, 2 H), 4.03 (s, 2 H), 3.94 (t, 2 H), 2.91 (s, 3 H), 2.40 (s, 3 H), 2.35 (m, 1 H), 2.27 (m, 2 H), 2.13 (m, 1 H), 1.91 (m, 2 H); MS (APCI+) m/z 702.9 (M+H)+.
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([F:29])[CH:28]=1)[CH2:6][C@H:7]([NH:22][C:23](=[O:25])[CH3:24])[C@H:8]([OH:21])[C@H:9]1[CH2:14][CH2:13][C@@H:12]([O:15][CH2:16][CH2:17][CH2:18][CH:19]=[CH2:20])[CH2:11][NH:10]1.[H][H]>[Pd].CO>[ClH:1].[F:29][C:27]1[CH:26]=[C:5]([CH:4]=[C:3]([F:2])[CH:28]=1)[CH2:6][C@H:7]([NH:22][C:23](=[O:25])[CH3:24])[C@H:8]([OH:21])[C@H:9]1[CH2:14][CH2:13][C@@H:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:11][NH:10]1
Reactant: [H][H]
Reactant: C=CCCCO[C@@H]1CC[C@H]([C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(C)=O)NC1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCCCCO[C@@H]1CC[C@H]([C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(C)=O)NC1
Yield: 86.2 %

Procedure:
Stir N-(1S,2R)-{1-(3,5-Difluoro-benzyl)-2-hydroxy-2-[(5R,2R)-5-pent-4-enyloxy-piperdin-2-yl]-ethyl}-acetamide hydrochloride (0.02 g, 0.04 mmol) and 10% Palladium on carbon (0.004 g, 0.004 mmol) in 2 mL methanol under a balloon of hydrogen at room temperature until all starting material is consumed. Filter the suspension through a pad of filtering agent and wash with methanol. Concentrate under reduced pressure to give the desired compound (0.015 g, 88%).
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]([OH:10])=O)=[CH:5][C:4]=1[CH3:11])=[O:2].[OH:12][CH2:13][C:14]([NH:16][CH2:17][C@H:18]([OH:33])[CH2:19][O:20][C:21]1[C:26]([CH3:27])=[CH:25][C:24]([C:28](=[NH:31])[NH:29]O)=[CH:23][C:22]=1[CH3:32])=[O:15]>>[CH:1]([C:3]1[S:7][C:6]([C:8]2[O:10][N:31]=[C:28]([C:24]3[CH:23]=[C:22]([CH3:32])[C:21]([O:20][CH2:19][C@@H:18]([OH:33])[CH2:17][NH:16][C:14](=[O:15])[CH2:13][OH:12])=[C:26]([CH3:27])[CH:25]=3)[N:29]=2)=[CH:5][C:4]=1[CH3:11])=[O:2]
Reactant: Cc1cc(C(=O)O)sc1C=O
Reactant: Cc1cc(C(=N)NO)cc(C)c1OC[C@@H](O)CNC(=O)CO
Product: Cc1cc(-c2nc(-c3cc(C)c(OC[C@@H](O)CNC(=O)CO)c(C)c3)no2)sc1C=O

Procedure:
The title compound is prepared according to Method A starting from 5-formyl-4-methyl-thiophene-2-carboxylic acid and (S)-2-hydroxy-N-{2-hydroxy-3-[4-(N-hydroxycarbamimidoyl)-2,6-dimethyl-phenoxy]-propyl}-acetamide; LC-MS*: tR=0.77 min; [M+1]+=445.92.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6][CH:5]=1.[NH2:14][CH2:15][N:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=[CH:17]1.[H][H]>[Pd].CO>[NH2:14][CH2:15][N:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=[CH:17]1.[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Agent: NCn1cnc2ccccc21
Solvent: CO
Product: COC(=O)c1ccc(N)cc1
Reaction time: 16 h
Yield: 96 %

Procedure:
To a parr shaker under nitrogen atmosphere was charged 3-aminomethylbenzimidazole-4 nitro benzoic acid methylester (10 g, 0.037 mol, 1.0 eq) and 180 ml of methanol. To the slurry was charged 1 g of 10% Palladium on carbon This was placed under 55 psi hydrogen atmosphere and shaken for 16 hours. The reaction was removed under nitrogen atmosphere and filtered over a bed of celite under an atmosphere of nitrogen and the celite/Pd/c washed with 500 ml of methanol (degassed with nitrogen) and the combined organics concentrated to an off white solid. Yield 96%.
Reaction SMILES: Cl[Si:2]([CH3:5])([CH3:4])[CH3:3].[CH2:6]([OH:10])[CH2:7][CH2:8][CH3:9].CN1C=CN=C1>>[CH3:3][Si:2]([CH3:5])([CH3:4])[O:10][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCO
Reactant: C[Si](C)(C)Cl
Agent: Cn1ccnc1
Product: CCCCO[Si](C)(C)C
Temperature: 0 °C
Yield: 89.4 %

Procedure:
4.40 g (40.5 mmol) of chlorotrimethylsilane were added dropwise to a solution of 3.00 g (40.5 mmol) of 1-butanol and 11.1 g (135 mmol) of 1-methylimidazole while stirring at 0° C. The reaction mixture was stirred for another 15 minutes at 0-5° C. and for 15 minutes at 20° C., resulting in the formation of a liquid two-phase mixture. The upper phase was separated off to give 5.30 g (theory: 5.93 g) of 1-trimethylsilyloxybutane as a colorless oil having a purity of 90% (GC).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[S:10][C:9]([C:15]([NH:17][NH2:18])=[O:16])=[N:8][C:7]=3[C:6]=2[CH:19]=1.[C:20]1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)C>C(OC)(OC)OC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[S:10][C:9]([C:15]4[O:16][CH:20]=[N:18][N:17]=4)=[N:8][C:7]=3[C:6]=2[CH:19]=1
Reactant: NNC(=O)c1nc2c(s1)CCOc1ccc(Br)cc1-2
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(OC)OC
Solvent: CCOCC
Product: Brc1ccc2c(c1)-c1nc(-c3nnco3)sc1CCO2
Temperature: 100 °C

Procedure:
To a solution of 9-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid hydrazide (400 mg) in trimethyl orthoformate (10 mL) was added p-toluenesulfonic acid (100 mg) and the reaction heated at 100° C. for 16 h. After cooling to room temperature, the solvent was reduced in vacuo and diethyl ether (10 mL) was added. The resulting solid was filtered and air-dried to give 9-bromo-2-[1,3,4]oxadiazol-2-yl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene.