Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1)[CH3:2].[N+:13]([O-])([O-:15])=[O:14].[K+].OS(O)(=O)=O>>[CH2:1]([C:3]1[C:12]([N+:13]([O-:15])=[O:14])=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc2cccnc2c1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCc1ccc2cccnc2c1[N+](=O)[O-]
Yield: 10.9 %

Procedure:
In a similar fashion using route 7 general procedure 15, 7-ethylquinoline (Intermediate 57) (1.21 g, 7.7 mmol), potassium nitrate (1.01 g, 10.0 mmol) and H2SO4 (3.6 ml) gave the title compound (170 mg, 12%) after purification by column chromatography with n-hexane/EtOAc (23:2-17:3) gradient elution.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[CH3:21][C:22]1[CH:27]=[C:26]([C:28](O)=[O:29])[CH:25]=[CH:24][N:23]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:28]([C:26]3[CH:25]=[CH:24][N:23]=[C:22]([CH3:21])[CH:27]=3)=[O:29])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:6][CH:7]=1
Reactant: Cc1cc(C(=O)O)ccn1
Reactant: Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Product: Cc1cc(C(=O)Nc2cnc(OCC(F)(F)F)c(-c3ccc(Cl)cc3)c2)ccn1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2, 2-trifluoro-ethoxy)-pyridin-3-ylamine and 2-methyl-4-pyridinecarboxylic acid, as starting materials, MS (LC/MS): 422.0 (M+H).
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:16]=1[CH:17]=O>>[Cl:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:16]=1[CH2:17][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: O=Cc1c(Cl)cccc1Cl
Reactant: O=c1cc(N2CCNCC2)nc[nH]1
Product: O=c1cc(N2CCN(Cc3c(Cl)cccc3Cl)CC2)nc[nH]1

Procedure:
6-[4-(2,6-Dichloro-benzyl)-piperazin-1-yl]-3H-pyrimidin-4-one was prepared using Procedure A from 6-piperazin-1-yl-3H-pyrimidin-4-one (Intermediate 4) and 2,6-dichlorobenzaldehyde (available from Fluka). Mass spectrum (ES) MH+=339.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([C:12]([NH:14][C@H:15]([C:20]([O:22]C)=[O:21])[CH2:16][CH:17]([CH3:19])[CH3:18])=[O:13])=[C:5]2[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[F:30][C:31]([F:44])([F:43])[O:32][C:33]1[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][CH:34]=1>>[CH3:11][N:7]1[C:8]2[C:4](=[CH:3][C:2]([NH:1][S:39]([C:36]3[CH:37]=[CH:38][C:33]([O:32][C:31]([F:44])([F:43])[F:30])=[CH:34][CH:35]=3)(=[O:41])=[O:40])=[CH:10][CH:9]=2)[C:5]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:6]1[C:12]([NH:14][C@H:15]([C:20]([OH:22])=[O:21])[CH2:16][CH:17]([CH3:18])[CH3:19])=[O:13]
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)c1c(-c2ccccc2)c2cc(N)ccc2n1C
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Product: CC(C)C[C@H](NC(=O)c1c(-c2ccccc2)c2cc(NS(=O)(=O)c3ccc(OC(F)(F)F)cc3)ccc2n1C)C(=O)O

Procedure:
The title compound was prepared from methyl N-[(5-amino-1-methyl-3-phenyl-1H-indol-2-yl)carbonyl]-L-leucinate and 4-trifluoromethoxybenzenesulfonyl chloride followed the procedure of Example 1 Step 3 as a brown solid: 1H NMR (DMSO-d6) δ 0.79 (d, J=6.3 Hz, 3H, 0.80 (d, J=6.3 Hz, 3H, 1.35-1.60 (m, 3H, 3.75 (s, 3H, 4.25-4.35 (m, 1H, 7.03 (dd, J=8.8, 2.0 Hz, 1H, 7.24 (d, J=1.4 Hz, 1H, 7.25-7.40 (m, 5H, 7.47 (d, J=8.9 Hz, 1H, 7.55 (d, J=7.9 Hz, 2H, 7.77 (d, J=7.9 Hz, 2H, 8.77 (d, J=7.9 Hz, 1H, 9.99 (s, 1H, 12.64 (br s, 1H; MS (ESI) m/z 604 (MH+), MS (ESI) m/z 602 [M-H]−; HRMS calcd for C29H29F3N3O6S: 604.1727; found (ESI+): 604.1716; Anal. calcd for C29H28F3N3O6S.0.4H2O: C, 57.02; H, 4.75; N, 6.96. Found: C, 56.70; H, 4.75; N, 6.94.
Reaction SMILES: ClC(Cl)(Cl)CO[C:5](=[O:15])[NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:8]=1[Cl:14].[NH2:18][C:19]1[CH:23]=[C:22]([C:24]([CH3:27])([CH3:26])[CH3:25])[NH:21][N:20]=1.O>CN(C=O)C>[C:24]([C:22]1[CH:23]=[C:19]([NH:18][C:5]([NH:6][C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:8]=2[Cl:14])=[O:15])[NH:20][N:21]=1)([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)c1cc(N)n[nH]1
Reactant: O=C(Nc1cccc(Cl)c1Cl)OCC(Cl)(Cl)Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(NC(=O)Nc2cccc(Cl)c2Cl)[nH]n1
Yield: 59.1 %

Procedure:
A solution of 2,2,2-trichloroethyl-2,3-dichlorophenylcarbamate (0.400 g, 1.19 mmol) and 3-amino-5-t-butylpyrazole (0.165 g, 1.19 mmol) in DMF (1 mL) was stirred at 80° C. overnight. Water (50 mL) was added and the mixture was extracted with EtOAc (3×100 mL), dried (MgSO4), concentrated and purified via column chromatography to yield 1-(3-t-butyl-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea (230 mg, 59% yield) as a pink foam. 1H NMR (400 MHz, CDCl3): δ 8.26 (d, J=6.8 Hz, 1H), 7.20-7.14 (m, 2H), 5.85 (brs, 1H), 1.34 (s, 9H), amine and urea protons not visible; MS (EI) m/z: 327.0 (M+H+).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[N-:12]=[N+:13]=[N-:14].[Na+].[Cl-].[NH4+]>CN(C)C=O.O>[N:12]([C:3]1[C:2]([Br:1])=[CH:7][N:6]=[C:5]2[NH:8][CH:9]=[CH:10][C:4]=12)=[N+:13]=[N-:14]
Reactant: Clc1c(Br)cnc2[nH]ccc12
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=Nc1c(Br)cnc2[nH]ccc12
Temperature: 110 °C
Yield: 43.1 %

Procedure:
5-Bromo-4-chloro-1H-pyrrolo[2,3-b]pyridine (1.5 g, 6.5 mmol), sodium azide (2.11 g, 32 mmol), and ammonium chloride (1.73 g, 32 mmol) were suspended in anhydrous dimethylformamide (10 mL). The reaction was heated to 110° C. for 19 h. The reaction mixture was diluted with water and the solids were collected. The solids were dissolved in a mixture of acetone and ethylacetate, the solution was filtered and concentrated to afford 4-Azido-5-bromo-1H-pyrrolo[2,3-b]pyridine (670 mg, 2.8 mmol, 43%). MS: m/z 238.0/240.0 (M+H+).
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[O:11][C@H:10]([C@@H:12]([CH2:14][OH:15])[OH:13])[C@H:8]([OH:9])[C@@H:6]1[OH:7])=[N+]=[N-]>CO.[Pd].C(OCC)(=O)C>[NH2:1][CH2:4][C@H:5]1[O:11][C@H:10]([C@@H:12]([CH2:14][OH:15])[OH:13])[C@H:8]([OH:9])[C@@H:6]1[OH:7]
Reactant: [N-]=[N+]=NC[C@H]1O[C@H]([C@H](O)CO)[C@H](O)[C@@H]1O
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: NC[C@H]1O[C@H]([C@H](O)CO)[C@H](O)[C@@H]1O
Reaction time: 24 h
Yield: 78.1 %

Procedure:
The azide (16) (0.12 g, 0.63 mmol) was stirred in methanol (5 ml) at room temperature under hydrogen in the presence of 10% palladium on carbon (10 mg). After 24 h, t.l.c. (5% methanol in ethyl acetate) indicated conversion of the starting material (Rf 0.3) to a single product (Rf 0.0). The reaction mixture was filtered through celite, the solvent removed in vacuo, and the resulting solid purified by ion exchange chromatography with Dowex 50W-X8 using 0.5M ammonia as eluant. After freeze drying, 1-amino-2,5-anhydro-1-deoxy-D-glycero-D-talo-heptitol (5) (95 mg, 88%) was obtained as a yellowish solid. The solid was taken up in water, and the solution neutralised with dilute aqueous hydrochloric acid. Freeze drying, followed by recrystallisation from methanol/chloroform, gave 1-amino-2,5-anhydro-1-deoxy-D-glycero-D-talo-heptitol hydrochloride (5) as a colourless crystalline solid, m.p. 189° C. (dec.). (Found: C, 36.61; H, 7.27; N, 5.42. C7H16O5NCl requires C, 36.61; H, 7.02; N, 6.10%); [α]D20 +38.6° (c 1.0 in CHCl3); δH (D2O) 3.00 (1H, dd, H-1, J1,1' 13.4 Hz, J1,2 8.8 Hz), 3.18 (1H, dd, H-1', J1',2 2.9 Hz), 3.52 (1H, dd, H-7, J6,7 5.0 Hz, J7,7' 12.1 Hz), 3.66 (1H, dd, H-7', J6,7' 2.7 Hz), 3.80 (1H, ddd, H-6, J5,6 9.0 Hz), 3.87 (1H, dd, H-5, J4,5 2.6 Hz), 3.91 (1H, dt, H-2, J2,3 8.4 Hz), 4.05 (1H, dd, H-3, J3,4 4.1 Hz), 4.17 (1H, dd, H-4); δC (D2O) 41.8, 63.1 (2×t, C-1, C-7), 69.0, 71.6, 74.3, 77.2, 79.6 (5×d, C-2, C-3, C-4, C-5, C-6); m/z (NH3, DCI) 194 (M+H+, 100%).
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].CO>O1CCCC1>[Br:1][CH2:2][C@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4]
Reactant: O=C(CBr)c1ccccc1
Solvent: CO
Solvent: C1CCOC1
Product: O[C@H](CBr)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84.6 %

Procedure:
(S)-2-amino-2-cyclohexyl-1,1-bis-(4-methoxyphenyl)ethanol (71.2 mg, 0.2 mmol), dry tetrahydrofuran (2 mL) and borane dimethylsulfide complex (1 00 μL, 1.0 mmol) were added to a dry flask under at atmosphere of nitrogen. The mixture was stirred at room temperature for 1.5 hours to form (R)-4-cyclohexyl-5,5-bis-(4-methoxy)phenyl-1,3,2-oxazaborolidine. A solution of bromoacetophenone (199 mg, 1.0 mmol) in dry tetrahydrofuran (4 mL) was added to the borane/(R)-4-cyclohexyl-5,5-bis-(4-methoxy)phenyl-1,3,2-oxazaborolidine complex at the rate of 9 mL/hr by means of a syringe pump. The resulting mixture was stirred at room temperature for an additional 1.5 hours. Methanol was added to quench the reaction and then the solvent was removed by evaporation. The resulting residue was chromatographed on silica gel (hexane/ethyl acetate, 25:1) and combination of the like fractions followed by removal of the solvent gave (S)-2-bromo-1-phenylethanol (170 mg, 96.6% ee). The enantiomeric excess was measured by HPLC (Chiralcel OD-H column, mobile phase, hexane/2-propanol 9:1, flow rate=0.7 mL/min).
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([N:11]2[C:15]3[CH:16]=[CH:17][C:18]([CH2:20][N:21]4[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]4)=[CH:19][C:14]=3[N:13]=[CH:12]2)=[N:8][C:7]=1[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=1)=[O:5])C.[OH-].[Li+]>O1CCCC1.O>[Cl:34][C:30]1[CH:29]=[C:28]([C:7]2[N:8]=[C:9]([N:11]3[C:15]4[CH:16]=[CH:17][C:18]([CH2:20][N:21]5[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26]5)=[CH:19][C:14]=4[N:13]=[CH:12]3)[S:10][C:6]=2[C:4]([OH:5])=[O:3])[CH:33]=[CH:32][CH:31]=1
Reactant: CCOC(=O)c1sc(-n2cnc3cc(CN4CCN(C)CC4)ccc32)nc1-c1cccc(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN1CCN(Cc2ccc3c(c2)ncn3-c2nc(-c3cccc(Cl)c3)c(C(=O)O)s2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.3 %

Procedure:
To a solution of 0.25 g (0.5 mmole) of 4-(3-chloro-phenyl)-2-[5-(4-methyl-piperazin-1-ylmethyl)-benzoimidazol-1-yl]-thiazole-5-carboxylic acid ethyl ester (I.2e) in 10 mL of tetrahydrofuran and 10 mL of water was added 0.12 g (5 mmole) of lithium hydroxide. The mixture was stirred at ambient temperature for 1 hour. The mixture was concentrated under reduced pressure, 40 mL of water was added and the pH adjusted to 6-7 by the addition of 1M hydrochloric acid. The precipitate was collected by filtration to give 0.120 g of 4-(3-chloro-phenyl)-2-[5-(4-methyl-piperazin-1-ylmethyl)-benzoimidazol-1-yl]-thiazole-5-carboxylic acid (I.3a) as a white solid.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([O:15]CC2C=CC=CC=2)[C:12]([C:23]([CH3:25])=[CH2:24])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:33][CH2:32][CH:31]([CH2:34][CH:35]=O)[CH2:30][CH2:29]1)=[O:27])C1C=CC=CC=1.S(C1C=CC(C)=CC=1)(O)(=O)=O.[CH:48]1([O:53][C:54](=[O:60])[C@H:55]([CH:57]([CH3:59])[CH3:58])[NH2:56])[CH2:52][CH2:51][CH2:50][CH2:49]1>>[OH:8][C:9]1[CH:14]=[C:13]([OH:15])[C:12]([CH:23]([CH3:24])[CH3:25])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:33][CH2:32][CH:31]([CH2:34][CH2:35][NH:56][C@H:55]([C:54]([O:53][CH:48]2[CH2:49][CH2:50][CH2:51][CH2:52]2)=[O:60])[CH:57]([CH3:58])[CH3:59])[CH2:30][CH2:29]1)=[O:27]
Reactant: CC(C)[C@H](N)C(=O)OC1CCCC1
Reactant: C=C(C)c1cc(C(=O)N2CCC(CC=O)CC2)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(C)c1cc(C(=O)N2CCC(CCN[C@H](C(=O)OC3CCCC3)C(C)C)CC2)c(O)cc1O

Procedure:
Prepared from Intermediate D and L-valine cyclopentyl ester tosylate. 1H NMR (300 MHz, d3-MeOD) 6.95 (1H, s), 6.34 (1H, s), 5.31-5.44 (1H, m), 4.08-4.35 (2H, m), 3.94 (1H, d, J=3.8 Hz), 3.05-3.25 (3H, m), 2.96 (2H, t, J=12.5 Hz), 2.26-2.42 (1H, m), 1.89-2.08 (3H, m), 1.61-1.88 (8H, m), 1.13-1.24 (12H, m) and 1.05 (6H, d, J=6.8 Hz) LC/MS: purity 85%, m/z 475 [M+H]+
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([CH3:13])=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].N([O-])=[O:15].[Na+]>S(=O)(=O)(O)O.O.C(OCC)(=O)C>[OH:15][C:2]1[CH:3]=[CH:4][C:5]([CH3:13])=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1cc(N)ccc1C
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1cc(O)ccc1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86.2 %

Procedure:
A mixture of ethyl 5-amino-2-methylbenzoate (14.4 g, 80.3 mmol) in aqueous 5% sulfuric acid (300 mL) was cooled with an ice-bath for 15 min. Sodium nitrite (6.09 g, 88.3 mmol) was then added dropwise as a solution in water (50 mL), and the resulting mixture stirred for at 0° C. for 30 min. After this time, the resulting mixture was heated to 60° C. for 18 h. The reaction mixture was then cooled to room temperature and diluted with ethyl acetate (150 mL). The organic layer was separated, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by flash chromatography (silica, gradient 0-40%, hexanes/ethyl acetate) afforded 12.48 g (86%) of ethyl 5-hydroxy-2-methylbenzoate as red-brown solid: 1H NMR (300 MHz, CDCl3) δ 7.44 (d, J=2.8 Hz, 1H), 7.10 (d, J=8.3 Hz, 1H), 6.91 (dd, J=8.3, 2.8 Hz, 1H), 5.44 (s, 1H), 4.35 (q, J=7.1 Hz, 2H), 2.50 (s, 3H), 1.38 (t, J=7.1 Hz, 3H); ESI MS m/z 181 [M+H]+.
Reaction SMILES: [C:1]([CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[C:20]2[C:15](=[CH:16][C:17]([S:21]([N:24](CC3C=CC(OC)=CC=3OC)[C:25]3[S:26][CH:27]=[CH:28][N:29]=3)(=[O:23])=[O:22])=[CH:18][CH:19]=2)[C:14]([F:41])=[CH:13][N:12]=1)#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[C:20]2[C:15](=[CH:16][C:17]([S:21]([NH:24][C:25]3[S:26][CH:27]=[CH:28][N:29]=3)(=[O:23])=[O:22])=[CH:18][CH:19]=2)[C:14]([F:41])=[CH:13][N:12]=1)#[N:2]
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccccc4OCC#N)ncc(F)c3c2)c(OC)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#CCOc1ccccc1-c1ncc(F)c2cc(S(=O)(=O)Nc3nccs3)ccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-(2-(cyanomethoxy)phenyl)-N-(2,4-dimethoxybenzyl)-4-fluoro-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (0.084 g, 0.141 mmol) was dissolved in DCM and TFA (0.1 mL, 1.298 mmol) was added. The reaction was stirred for 30 minutes at room temperature. The reaction was concentrated and purified via column chromatography (RediSep Gold 12 g, gradient elution 0-10% MeOH:DCM) to afford 1-(2-(cyanomethoxy)phenyl)-4-fluoro-N-(thiazol-2-yl)isoquinoline-6-sulfonamide as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ=13.00 (br. s., 1H), 8.74 (d, J=1.6 Hz, 1H), 8.51 (d, J=1.6 Hz, 1H), 7.98 (dd, J=1.7, 8.9 Hz, 1H), 7.77 (d, J=8.8 Hz, 1H), 7.69-7.59 (m, 1H), 7.48-7.36 (m, 2H), 7.34-7.22 (m, 2H), 6.89 (d, J=4.4 Hz, 1H), 5.09 (s, 2H). m/z (ESI) 441.0 (M+H)+.
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:34])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20]I)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:22])[C:12]=2[C@H:23]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]([O:26]CC)=[O:25])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].[CH3:35][C:36]1[CH:37]=[CH:38][C:39]([O:44][C@H:45]([CH2:47][CH:48]=[CH2:49])[CH3:46])=[C:40]([CH2:42][OH:43])[CH:41]=1.[H-].[Na+]>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:4][C:5]1([CH3:34])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][O:43][CH2:42][C:40]4[CH:41]=[C:36]([CH3:35])[CH:37]=[CH:38][C:39]=4[O:44][C@H:45]([CH2:47][CH:48]=[CH2:49])[CH3:46])[CH:19]=[C:15]3[N:14]=[C:13]([CH3:22])[C:12]=2[C@H:23]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])[C:24]([OH:26])=[O:25])[CH2:7][CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CC[C@H](C)Oc1ccc(C)cc1CO
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(CI)nn23)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)O)c(C)nc3cc(COCc4cc(C)ccc4O[C@@H](C)CC=C)nn23)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 15.2 %

Procedure:
To a solution of (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(iodomethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.20 g, 0.342 mmol) and (S)-(5-methyl-2-(pent-4-en-2-yloxy)phenyl)methanol (0.085 g, 0.411 mmol) in DMF (4 ml) was added sodium hydride (0.021 g, 0.513 mmol) and the mixture was stirred at rt. After 5 h, the reaction was diluted with EtOAc and washed with 1N HCl, water then brine. The organic phase was dried (Na2SO4), filtered and concentrated. The yellow residue was purified by flash chromatography (Biotage; 10% MeOH/DCM; 10 CV) to give (S)-2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-5-methyl-2-(((5-methyl-2-((S)-pent-4-en-2-yloxy)benzyl)oxy)methyl)pyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetic acid (32.7 mg, 0.052 mmol, 15.05% yield) as a pale yellow oil. LCMS (M+H) calcd for C36H51N4O6: 635.38. found: 635.5.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:17])[CH2:9][CH2:10]/[CH:11]=[CH:12]/[C:13]([O:15][CH3:16])=[O:14])[O:5][C:4](=[O:18])[C:3]=1[C:19](=[O:22])[CH2:20][CH3:21].CCN(C(C)C)C(C)C.[CH3:32]/[C:33](/[CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[CH:34]\[CH:35]=O>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:21]/[C:20](=[CH:35]\[CH:34]=[C:33]([CH3:32])[CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])/[C:19]([C:3]1[C:4](=[O:18])[O:5][C:6]([CH:8]([CH3:17])[CH2:9][CH2:10]/[CH:11]=[CH:12]/[C:13]([O:15][CH3:16])=[O:14])=[CH:7][C:2]=1[OH:1])=[O:22]
Reactant: CCC(=O)c1c(O)cc(C(C)CC/C=C/C(=O)OC)oc1=O
Reactant: CCCCC/C(C)=C/C=O
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCCC(C)=C/C=C(\C)C(=O)c1c(O)cc(C(C)CC/C=C/C(=O)OC)oc1=O
Reaction time: 0.33 h

Procedure:
To (E)-methyl 6-(4-hydroxy-2-oxo-3-propionyl-2-H-pyran-6-yl)hept-2-enoate (VII; 0.63 g, 2.05 mmol) in 30 ml anhydrous CH2Cl2 at −72° C., was added titanium tetrachloride (0.88 ml; 8 mmol; Aldrich) under argon, and the reaction mixture was stirred for 20 min. DIPEA (1.64 ml; 9.43 mmol; Aldrich) was added, and the reaction mixture was stirred for 90 min. (E)-3-methyl-octenal (XXI; 1 g; 7.25 mmol) in 5 ml anhydrous CH2Cl2 was added in two portions over 10 min, and the reaction mixture was stirred at −72° C. for 48 h and at 0° C. for 1 hour. The reaction was quenched with 40 ml ice water and extracted with 2×40 ml CH2Cl2. The CH2Cl2 extracts were pooled, washed with saturated NH4Cl, washed twice with saturated NaHCO3, and dried with anhydrous Na2SO4. The product was purified by silica flash chromatography (EtOAc gradient in hexanes).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH2:14].[Cl:15][C:16]1[CH:17]=[C:18]([CH:24]=[CH:25][CH:26]=1)/[CH:19]=[CH:20]/[C:21](Cl)=O.Cl>CO>[ClH:15].[Cl:15][C:16]1[CH:17]=[C:18]([CH:24]=[CH:25][CH:26]=1)/[CH:19]=[CH:20]/[C:21]1[N:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:14]=1
Reactant: O=C(Cl)/C=C/c1cccc(Cl)c1
Reactant: Nc1ccccc1Nc1ccccn1
Agent: Cl
Solvent: CO
Product: Clc1cccc(/C=C/c2nc3ccccc3n2-c2ccccn2)c1

Procedure:
Free base of the titled compound was prepared from N-(2-pyridyl)-o-phenylenediamine and (E)-3-Chlorocinnamoyl chloride (Amino, Y.; Kawada, K.; Toi, K.; Kumashiro, I.; Fukushima, K. Chem. Pharm. Bull, 1988, 36, 4426) according to the preparation of (E)-1-(2-pyridyl)-2-styryl-H-benzimidazole (Example 1, method A). The free base was dissolved with a 10% methanol solution of hydrogen chloride (5 ml). Concentration and recrystallization from ethyl acetate/ethanol yielded the titled compound. MW: 368.27; mp:>230° C.; 1H-NMR (DMSO) δ: 8.85-8.81 (1H, m), 8.31-8.22 (1H, m), 8.20 (1H, d, J=16.1 Hz), 7.90-7.81 (3H, m), 7.78-7.72 (1H, m), 7.68-7.43 (6H, m), 7.33 (1H, d, J=16.1 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:11]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:13]([C:22]#[N:23])=[CH:12]2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].CC1(C)[O:30][C:29]([C:31]2[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=2)[C:34]#[N:35])=[CH:28][C:27](=O)[O:26]1>>[C:34]([C:33]1[CH:32]=[C:31]([C:29](=[O:30])[CH2:28][C:27]([NH:1][C:2]2[CH:3]=[C:4]([N:11]3[CH:15]=[C:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:13]([C:22]#[N:23])=[CH:12]3)[CH:5]=[CH:6][C:7]=2[N+:8]([O-:10])=[O:9])=[O:26])[CH:38]=[CH:37][CH:36]=1)#[N:35]
Reactant: N#Cc1cn(-c2ccc([N+](=O)[O-])c(N)c2)cc1-c1ccccc1
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Product: N#Cc1cccc(C(=O)CC(=O)Nc2cc(-n3cc(C#N)c(-c4ccccc4)c3)ccc2[N+](=O)[O-])c1

Procedure:
The title compound was prepared from 1-(3-amino-4-nitro-phenyl)-4-phenyl-1H-pyrrole-3-carbonitrile (Example E3) (254 mg, 0.835 mmol) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example L1) (210 mg, 0.919 mmol) according to the general procedure M. Obtained as an orange solid (287 mg).
Reaction SMILES: [C:1]1(=[O:34])[N:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13](=[O:28])[C:14](=[CH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=2)[C:15]([CH3:17])=O)[C:4](=[O:29])[C:3]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:2]12.[CH3:35][O:36][C:37](=[O:42])/[CH:38]=[C:39](\[NH2:41])/[CH3:40]>C(O)(C)C>[CH3:40][C:39]1[NH:41][C:15]([CH3:17])=[C:14]([C:13]([O:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][N:5]2[C:1](=[O:34])[C:2]3=[CH:33][CH:32]=[CH:31][CH:30]=[C:3]3[C:4]2=[O:29])=[O:28])[CH:18]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=2)[C:38]=1[C:37]([O:36][CH3:35])=[O:42]
Reactant: CC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(=O)OCCCCCCN1C(=O)c2ccccc2C1=O
Reactant: COC(=O)/C=C(/C)N
Solvent: CC(C)O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCCCCN2C(=O)c3ccccc3C2=O)C1c1cccc([N+](=O)[O-])c1

Procedure:
12.0 g (26 mmol) of 2-(3-nitrobenzylidene)-acetoacetic acid-(6-phthalimidohexyl)ester and 3.0 g (26 mmol) of 3-amino-crotonic acid methyl ester are boiled under reflux in 100 ml of isopropanol for 4 hours. After removal of the solvent by evaporation under vacuum, 15.0 g of a brownish yellow oil suitable for reactions without further purification are obtained.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][CH:6]=1)=[O:4].[C:15]([O-:18])(=[O:17])[CH3:16].[Na+]>CN(C=O)C>[C:15]([O:18][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][CH:6]=1)=[O:4])(=[O:17])[CH3:16]
Reactant: CS(=O)(=O)c1ccc(C(=O)CBr)cc1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OCC(=O)c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-Bromo-1-[4-(methylsulfonyl)phenyl]ethanone (2.4 g, 8.7 mmol) was added over a period of 30 min to the suspension of sodium acetate (0.7 g, 8.7 mmol) in DMF (25 mL) at RT. The mixture was stirred at 25° C. for 16 h, and was partitioned between H2O (100 mL) and EtOAc/hexane (20/100 mL). The organic layer was separated and washed with water (3×100 mL), dried with anhydrous Na2SO4, and concentrated to give 2-[4-(methylsulfonyl)phenyl]-2-oxoethyl acetate. LCMS: m/e=256 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:13][C@@H:14]1[CH2:19][CH2:18][C@H:17]([C:20]([O:22]CC)=[O:21])[CH2:16][C@H:15]1[NH:25][C:26]([C:28]1[S:29][C:30]3[CH2:31][N:32]([CH3:37])[CH2:33][CH2:34][C:35]=3[N:36]=1)=[O:27])=[O:12])=[CH:5]2.C(O)C.[OH-].[Na+].Cl>O1CCCC1>[C:20]([C@H:17]1[CH2:18][CH2:19][C@@H:14]([NH:13][C:11]([C:6]2[NH:7][C:8]3[C:4]([CH:5]=2)=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=3)=[O:12])[C@H:15]([NH:25][C:26]([C:28]2[S:29][C:30]3[CH2:31][N:32]([CH3:37])[CH2:33][CH2:34][C:35]=3[N:36]=2)=[O:27])[CH2:16]1)([OH:22])=[O:21]
Reactant: CCOC(=O)[C@H]1CC[C@@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)[C@H](NC(=O)c2nc3c(s2)CN(C)CC3)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CN1CCc2nc(C(=O)N[C@@H]3C[C@@H](C(=O)O)CC[C@H]3NC(=O)c3cc4cc(Cl)ccc4[nH]3)sc2C1
Reaction time: 12 h
Yield: 78.4 %

Procedure:
(1R,2R,4S)—N1-[(5-Chloroindol-2-yl)carbonyl]-4-ethoxycarbonyl-N2-[(5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexane-diamine (1.6 g) was suspended in a mixed solvent of ethanol (20 ml) and tetrahydrofuran (15 ml), and a 1N aqueous solution (5.9 ml) of sodium hydroxide was added at room temperature to stir the mixture for 12 hours at the same temperature. After adding 1N hydrochloric acid (5.9 ml), the solvent was distilled off under reduced pressure, and the residue was washed with water and ether to obtain the title compound (1.19 g) as a colorless solid.