Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:20](OC)=[O:21])[CH:16]=2)[CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCCCCC.CO>ClCCl>[C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:20][OH:21])[CH:16]=2)[CH2:11]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc2c(c1)CCC(CNC(=O)OC(C)(C)C)C2
Solvent: CO
Solvent: ClCCl
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)NCC1CCc2cc(CO)ccc2C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 72.3 %

Procedure:
In dichloromethane (10 ml), the (2RS)-2-(N-tert-butoxycarbonylaminomethyl)-6-methoxycarbonyl-1,2,3,4-tetrahydronaphthalene (0.47 g) was dissolved. Aluminum diisobutylhydride (a 0.95M hexane solution, 3.60 ml) was added dropwise to the resulting solution at an external temperature of −78° C., followed by stirring for 90 minutes without changing the temperature. Methanol was added to the reaction mixture and the mixture was heated to room temperature. The insoluble matter was filtered off from filtration through Celite. The filtrate was concentrated under reduced pressure. The concentrate was diluted with dichloromethane, washed with water and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by chromatography on a silica gel column (hexane:ethyl acetate 3:1), whereby colorless crystals (0.31 g, 72%) was obtained. A portion of the resulting crystals was recrystallized from a mixed solvent of hexane and ethyl acetate, whereby colorless crystals were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:4]([C:5]([OH:7])=O)[C:3]=1[OH:12].[Cl:13][C:14]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:15]=1[NH2:16]>>[Cl:1][C:2]1[C:3]([OH:12])=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5]([NH:16][C:15]1[CH:17]=[CH:18][C:19]([N+:21]([O-:23])=[O:22])=[CH:20][C:14]=1[Cl:13])=[O:7]
Reactant: O=C(O)c1cc(Cl)cc(Cl)c1O
Reactant: Nc1ccc([N+](=O)[O-])cc1Cl
Product: O=C(Nc1ccc([N+](=O)[O-])cc1Cl)c1cc(Cl)cc(Cl)c1O

Procedure:
This material was prepared according to the method of Example 1 using 3,5-dichlorosalicylic acid and 2-chloro-4-nitroaniline, with reagents and solvents employed in similar molar ratios. 1HNMR (500 MHz, DMSO-d6): δ7.85 (m, 1H, H4), 7.98 (m, 1H, H5), 8.29 (m, 1H, H5′), 8.04 (m, 1H, H6), 8.44 (m, 1H, H3′), 8.55 (m, 1H, H6′).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=[CH:7]2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[F:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1>C(Cl)Cl>[F:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([N:1]2[CH2:6][CH2:5][C:4]3([C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[CH:8]=[CH:7]3)[CH2:3][CH2:2]2)(=[O:31])=[O:30])=[CH:25][CH:24]=1
Reactant: C1=CC2(CCNCC2)c2ccccc21
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccc(F)cc1)N1CCC2(C=Cc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Spiro(1H-indene-1,4'-piperidine) (40 mg, 0.18 mmol) was suspended in CH2Cl2 (2 ml) and treated with triethylamine (52.6 μl, 0.378 mmol) followed by 4-fluorobenzenesulfonyl chloride (38.6 mg, 0.198 mmol). The reaction was stirred 1 hr at ambient temperature and chromatographed on a silica gel column eluted with 20% hexane in CH2Cl2. The product fractions were evaporated to dryness in vacuo and the residue crystallized from ether to provide the title compound: (mp 169°-174°).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[N:9][N-:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[Na+].Br[CH2:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=1.CC(C)=O.C(OCC)(=O)C>[Cl-].[Na+].O.CCCCCC>[N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[N:9][N:10]2[CH2:15][C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2cn[n-]c2c1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: COC(=O)c1ccc(Cn2ncc3ccc([N+](=O)[O-])cc32)cc1

Procedure:
A mixture of 3.7 g. sodium 6-nitroindazolide, 4.58 g. of methyl 4-bromomethylbenzoate (F) and 120 ml. acetone was heated under reflux in a nitrogen atmosphere for 54 hours and then diluted with 250 ml. ethyl acetate and 40 ml. of 50% w/v brine. The organic layer was separated, washed with brine, dried (MgSO4), and evaporated to give a brown solid. Early fractions from chromatography of the solid on a Waters 500 HPLC (SiO2, 25% v/v ethyl acetate in hexane) yielded a solid which was crystallized from ethyl acetate to give methyl 4-(6-nitroindazol-1-yl)methylbenzoate (J) as light yellow needles, 1.71 g. (28%); m.p. 171°-172.5° C.; partial 13C-NMR: 134.10 (C-3).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([C:13]([OH:15])=O)[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.C(=O)(O)[O-].[Na+].[NH:35]1[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2[N:37]=[C:36]1[C:44]1[C:52]2[C:47](=[CH:48][CH:49]=[C:50]([NH2:53])[CH:51]=2)[N:46]([CH:54]2[CH2:59][CH2:58][CH2:57][CH2:56][O:55]2)[N:45]=1>CN(C=O)C>[NH:37]1[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[N:35]=[C:36]1[C:44]1[C:52]2[C:47](=[CH:48][CH:49]=[C:50]([NH:53][C:13]([CH:10]3[CH2:9][CH2:8][N:7]([C:4]4[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=4)[CH2:12][CH2:11]3)=[O:15])[CH:51]=2)[N:46]([CH:54]2[CH2:59][CH2:58][CH2:57][CH2:56][O:55]2)[N:45]=1
Reactant: O=C(O)C1CCN(c2ccncc2)CC1
Reactant: Nc1ccc2c(c1)c(-c1nc3ccccc3[nH]1)nn2C1CCCCO1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(Nc1ccc2c(c1)c(-c1nc3ccccc3[nH]1)nn2C1CCCCO1)C1CCN(c2ccncc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 39 %

Procedure:
1-(Pyridin-4-yl)piperidine-4-carboxylic acid (14 mg, 0.068 mmol), HOBt (12 mg, 0.088 mmol), EDC (17 mg, 0.088 mmol) and sodium bicarbonate (5 mg, 0.059 mmol) were added to a solution of 3-(1H-benzo[d]imidazol-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine (20 mg, 0.059 mmol) in DMF (5 mL). The reaction mixture was stirred at room temperature for 24 h, and then the solvent was removed in vacuum. Purification by flash chromatography (6% CH3OH/CH2Cl2) afforded the title compound (12 mg).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].[OH-].[Na+].[C:12]([O:16][C:17](=O)[O:18]C(C)(C)C)([CH3:15])([CH3:14])[CH3:13]>O.C(O)(C)(C)C>[CH3:13][C:12]([CH3:15])([O:16][C:17]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])=[O:18])[CH3:14]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: NCCCCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)(C)O
Solvent: O
Product: CC(C)(C)OC(=O)NCCCCCC(=O)O
Temperature: 25 °C
Reaction time: 48 h
Yield: 103.8 %

Procedure:
6-Aminocaproic acid (14.4 g, 110 mmol, 1.1 eq.) was treated with sodium hydroxide (4.4 g, 110 mmol) dissolved in 11 mL of water. t-Butanol (22 mL) was added resulting in a suspension which was next treated with di-tertbutylcarbonate (21.8 g, 100 mmol) dissolved in t-butanol (22 mL). The reaction mixture, which remained a suspension, was stirred for 48 hours at room temperature, then treated with water (75 mL), giving a clear solution. The aqueous solution was then rinsed with two portions of petroleum ether (250 mL), then cooled in an ice-bath and acidified to pH 2 with solid potassium hydrogen sulfate. The acidified aqueous layer was extracted twice with portions of ethyl acetate (250 mL). The combined organic extract was rinsed with two 50 mL portions of water and brine, then dried over anhydrous magnesium sulfate and concentrated in vacuo. Trituration of the crude product (24 g) afforded 21.67 g of the title C compound, m.p. 39°-42° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8](=[S:28])[NH:9][C:10]=2[C:11]2[C:20]([F:21])=[C:19]3[C:14]([CH:15]=[CH:16][C:17]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[N:18]3)=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.Br[C:30]1[S:31][CH:32]=[N:33][N:34]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>>[F:21][C:20]1[C:11]([C:10]2[N:9]=[C:8]([S:28][C:30]3[S:31][CH:32]=[N:33][N:34]=3)[N:4]3[CH:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]=23)=[CH:12][CH:13]=[C:14]2[C:19]=1[N:18]=[C:17]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH:16]=[CH:15]2
Reactant: Nc1nccn2c(=S)[nH]c(-c3ccc4ccc(-c5ccccc5)nc4c3F)c12
Reactant: Brc1nncs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1nccn2c(Sc3nncs3)nc(-c3ccc4ccc(-c5ccccc5)nc4c3F)c12
Temperature: 100 °C

Procedure:
A 10 mL microwave vessel was charged with a solution of 8-amino-1-(8-fluoro-2-phenyl-quinolin-7-yl)-2H-imidazo[1,5-a]pyrazine-3-thione (20 mg, 0.00005 mol), 2-bromo-1,3,4-thiadiazole (0.017 g, 0.00010 mol) and potassium carbonate (0.021 g, 0.00015 mol) in DMF (1.4 mL, 0.018 mol). The reaction mixture was heated in the microwave at 100° C. for 10 min. The reaction mixture was concentrated in vacuo and purification by Gilson HPLC eluting with 10→65% acetonitrile: H2O afforded the title compound as a light yellow solid. 1H NMR (400 MHz, CDCl3): δ=7.31 (d, J=5.05 Hz, 1H), 7.47-7.58 (m, 3H), 7.69-7.80 (m, 3H), 8.05 (d, J=8.84 Hz, 1H), 8.24 (dd, J=8.34, 1.52 Hz, 2H), 8.32 (dd, J=8.72, 1.39 Hz, 1H), 9.07 (s, 1H). MS(ES+): m/z 472.13 (100)[MH+]. HPLC: tR=2.9 min (Open Lynx polar—5 min).
Reaction SMILES: [C:1]([NH2:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH:11]([CH2:19][CH3:20])[C:12](=O)[C:13]([O:15]CC)=[O:14]>C1(C)C=CC=CC=1>[CH2:19]([C:11]1[O:8][C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:9][C:12]=1[C:13]([OH:15])=[O:14])[CH3:20]
Reactant: CCOC(=O)C(=O)C(Br)CC
Reactant: NC(=O)c1ccccc1
Solvent: Cc1ccccc1
Product: CCc1oc(-c2ccccc2)nc1C(=O)O
Yield: 8.4 %

Procedure:
Intermediate 1E was prepared (as described below for the preparation of intermediate 2B) from 4.08 g of benzamide, 5.0 g of ethyl 3-bromo-2-oxo-pentanoate, and 10 mL of toluene. Solids were collected and washed with cold water after cooling of the NaOH solution. Heating these solids with citric acid as described followed by cooling and isolation of the resulting solids gave 410 mg (9% yield) of the title compound; 1H NMR (CDCl3, 300 MHz) δ8.06-8.03 (m, 2H), 7.49-7.43 (m, 3H), 3.14 (q, 2H, J=8.0), 1.34 (t, 3H, J=8.0); low resolution MS (ES+)m/e 217.8 (MH+).
Reaction SMILES: [Na].[CH:2]([CH:4]([CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:5]([O:7]CC)=O)=O.[C:17]1(/[CH:23]=[CH:24]/[C:25](=[NH:27])[NH2:26])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CO>CCO>[OH:7][C:5]1[C:4]([CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:2][N:27]=[C:25](/[CH:24]=[CH:23]/[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:26]=1
Reactant: N=C(N)/C=C/c1ccccc1
Reactant: CCOC(=O)CCC(C=O)C(=O)OCC
Agent: [Na]
Solvent: CCO
Solvent: CO
Product: CCOC(=O)CCc1cnc(/C=C/c2ccccc2)nc1O
Yield: 59.9 %

Procedure:
Diethyl α-formylglutarate sodium salt (1 g, 4.2 mmol) and (2E)-3-phenyl-2-propenimidamide (0.61 g, 4.2 mmol), prepared in Example 126 (g), were combined in EtOH (20 mL) and MeOH (10 mL) and heated at reflux for 12 h. The solvent was removed and the resulting solid triturated with ether and filtered to give the desired product as a yellow solid (0.75 g, 56%). The mother liquor contained additional product which was not isolated. LCMS (ES+) m/z 299 (MH+).
Reaction SMILES: C(OC([NH:11][C@H:12]([C:17]([NH:19][C@@H:20]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C@H:21]([OH:38])[CH2:22][N:23]1[C@H:27]([C:28]([NH:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:26][C@@H:25]2[CH2:35][CH2:36][CH2:37][C@H:24]12)=[O:18])[CH2:13][C:14](=[O:16])[NH2:15])=O)C1C=CC=CC=1>C(O)C.[Pd]>[NH2:11][C@H:12]([C:17]([NH:19][C@@H:20]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C@H:21]([OH:38])[CH2:22][N:23]1[C@H:27]([C:28]([NH:30][C:31]([CH3:33])([CH3:34])[CH3:32])=[O:29])[CH2:26][C@@H:25]2[CH2:35][CH2:36][CH2:37][C@H:24]12)=[O:18])[CH2:13][C:14](=[O:16])[NH2:15]
Reactant: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCC[C@@H]2N1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCC[C@@H]2N1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(N)=O
Yield: 100.2 %

Procedure:
A solution of 397 mg of 1-[3(S)-[[N-(benzyloxycarbonyl)-L-asparaginyl]amino]-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-octahydro-(3aS,6aS)-cyclopenta[b]pyrrole-2(S)-carboxamide in 20 ml of ethanol was hydrogenated over 10% palladium-on-carbon at 20° C. and under atmospheric pressure for 4 hours, The catalyst was removed by filtration and the filtrate was evaporated to give 312 mg of 1-[3(S)-[[L-asparaginyl]amino]-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-octahydro-(3aS,6aS)-cyclopenta[b]pyrrole-2(S)-carboxamide as a pale yellow gum; m/e 488 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH:4]([N:16]1[CH2:21][CH2:20][NH:19][CH:18]([CH2:22][CH3:23])[CH2:17]1)[CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1.[CH3:25][C:26]([O:29][C:30]([NH:32][C@@H:33]([C:42](O)=[O:43])[CH2:34][C:35]1[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=1)=[O:31])([CH3:28])[CH3:27].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C.O.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:24])[CH:4]([N:16]1[CH2:21][CH2:20][N:19]([C:42](=[O:43])[CH:33]([NH:32][C:30]([O:29][C:26]([CH3:27])([CH3:25])[CH3:28])=[O:31])[CH2:34][C:35]2[CH:36]=[CH:37][C:38]([Cl:41])=[CH:39][CH:40]=2)[CH:18]([CH2:22][CH3:23])[CH2:17]1)[CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)O
Reactant: CCC1CN(C(Cc2ccc3ccccc3c2)C(=O)OC)CCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: CCC1CN(C(Cc2ccc3ccccc3c2)C(=O)OC)CCN1C(=O)C(Cc1ccc(Cl)cc1)NC(=O)OC(C)(C)C
Temperature: 0 °C

Procedure:
2-(3-Ethyl-piperazin-1-yl)-3-naphthalen-2-yl-propionic acid methyl ester, 34, (0.52 g, 1.6 mmol) and Boc-D-4-chlorophenylalanine (0.5 g, 1.7 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluoro-phosphate (1.2 g, 3.2 mmol) are dissolved in anhydrous DMF (20 mL). The reaction mixture is cooled to 0° C., then N-methylmorpholine (0.35 mL, 3.2 mmol) is added. The reaction mixture is placed in a refrigerator overnight. EtOAc (75 mL) and water (100 mL) are added, and the organic layer is separated. The aqueous layer is extracted with EtOAc (3×50 mL). All organic layers are combined and washed with water (20 mL), and dried over Na2SO4. The organic layers are concentrated in vacuo to afford 1.0 g (quantitative yield) of the desired product. 1H NMR (CDCl3, δ): 7.70–7.65 (m, 3H), 7.52 (s, 1H), 7.35–7.32 (m, 2H), 7.22–7.13 (m, 4H), 7.07–7.02 (m, 2H), 5.59 (dd, J=13.5, 8.7 Hz, 1H), 4.74 (q, J=7.5 Hz, 1H), 2.28–4.21 (m, 1H), 3.53 (d, J=12.3 Hz, 3H), 3.42–3.08 (m, 2H), 3.04–2.81 m, 4H), 2.80 (s, 1H), 2.75 (s, 3H), 2.64–2.60 (m, 1H), 2.46 (t, J=10.5 Hz, 1H), 2.20–2.05 (m, 1H), 1.55–1.40 (m, 1H), 1.18 (s,9H), 0.54–0.47 (m, 2H); 13C NMR, δ 171.6, 170.5, 170.0, 162.9, 155.0, 150.7, 135.8, 135.2, 133.6, 132.8, 132.4, 131.1, 131.2, 128.9, 128.7, 128.6, 128.0, 127.7, 127.6, 126.2, 125.6, 124.5, 120.4, 79.7, 68.9, 60.5, 55.8, 53.7, 51.4, 51.0, 47.4, 47.0, 41.5, 40.0, 39.0, 38.7, 38.0, 36.6, 35.3, 35.0, 31.6, 28.4, 22.8, 21.8, 21.1, 14.3,10.5, 10.0.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([OH:11])[CH:9]=2)[CH2:4][CH2:3][CH2:2]1.B(Cl)(Cl)Cl.CS[C:18]#[N:19].[Cl-].[Cl-].[Cl-].[Al+3].[OH-].[Na+]>ClC(Cl)C.O>[OH:11][C:8]1[CH:9]=[C:10]2[C:5]([CH2:4][CH2:3][CH2:2][O:1]2)=[CH:6][C:7]=1[C:18]#[N:19]
Reactant: CSC#N
Reactant: Oc1ccc2c(c1)OCCC2
Agent: ClB(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Solvent: O
Product: N#Cc1cc2c(cc1O)OCCC2
Temperature: 25 °C
Reaction time: 17 h

Procedure:
In a 250 mL round-bottom flask was placed Chroman-7-ol (1.8 g, 12.0 mmol, from Step 3-1-2) in dry dichloroethane (30 mL ) under argon. The solution was cooled to 0° C. where boron trichloride (13.2 mL, 1M in CH2Cl2, 13.2 mmol, 1.1 eq) was added dropwise. At this point, methyl thiocyanate (0.97 g, 13.2 mmol, 1.1 eq) was added followed by aluminum trichloride (1.6 g, 12.0 mmol, 1 eq). The reaction was allowed to warm up to rt and stirred for 17 h. The reaction mixture was cooled down to 0° C. and 10 mL of 50% w/w NaOH was added to adjust the solution to PH˜14, followed by 40 mL of water. The solution was then refluxed at 65° C. for 2 h. The solution was allowed to cool to ambient temperature. The aqueous layer was washed with dichloromethane (20 mL). The aqueous solution was then transferred to an Erlenmeyer flask and acidified to pH˜1 with conc. HCl (aq.). This solution was extracted with EtOAc (3×20 mL) and the combined organic layers were dried over Na2SO4, filtered and evaporated. The residue was suspended in cold CH2Cl2 and filtered. The filtrate was concentrated and the suspension procedure was repeated until no further solid precipitated. The combined solids were found to be nearly pure product with minor contaminants. The desired product was white solid (1.20 g, 54.3%). 1H-NMR (CD3CN) δ 7.87 (s, 1H, OH), 7.25 (s, 1H), 6.35 (s, 1H), 4.21 (t, 2H), 2.70 (t, 2H), 1.98 (m, 2H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:31]=[CH:30][C:8]2[N:9]([C:12]3[CH:13]=[C:14]([NH:26][C:27](=[O:29])[CH3:28])[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=4[F:25])[CH:17]=3)[CH:10]=[N:11][C:7]=2[CH:6]=1)=O.[NH2:32][C:33]([NH2:35])=[S:34]>C(O)C>[NH2:35][C:33]1[S:34][C:3]([C:5]2[CH:31]=[CH:30][C:8]3[N:9]([C:12]4[CH:13]=[C:14]([NH:26][C:27](=[O:29])[CH3:28])[CH:15]=[C:16]([C:18]5[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=5[F:25])[CH:17]=4)[CH:10]=[N:11][C:7]=3[CH:6]=2)=[CH:2][N:32]=1
Reactant: NC(N)=S
Reactant: CC(=O)Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(C(=O)CBr)ccc32)c1
Solvent: CCO
Product: CC(=O)Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(-c4cnc(N)s4)ccc32)c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 14.7 %

Procedure:
To a solution of N-(5-(5-(2-bromoacetyl)-1H-benzo[d]imidazol-1-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)acetamide (100 mg, 0.20 mmol) in ethanol was added thiourea (20 mg, 0.30 mmol, 1.5 eq). The mixture was stirred at 60° C. for 3 h. The mixture was quenched and extracted as in Example 1(d). The solvent was distilled off to give the crude residue which was purified by preparative HPLC to give the product in 14.7% yield (14 mg). 1H NMR (300 MHz, CD3OD): δ 8.73 (s, 1H), 8.11 (s, 1H), 8.01 (s, 1H), 7.73-7.69 (m, 2H), 7.62-7.50 (m, 2H), 7.45 (d, 1H), 7.10-6.99 (m, 3H), 2.10 (s, 3H); LC-MS (ESI): Calculated mass: 461.4; Observed mass: 462.1 [M+H]+ (rt: 0.80 min).
Reaction SMILES: N#N.[Br:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][OH:9])=[C:6]([F:12])[C:5]=1[F:13].CCN(CC)CC.[S:21](Cl)([CH3:24])(=[O:23])=[O:22]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:24][S:21]([O:9][CH2:8][C:7]1[CH:10]=[CH:11][C:4]([Br:3])=[C:5]([F:13])[C:6]=1[F:12])(=[O:23])=[O:22]
Reactant: OCc1ccc(Br)c(F)c1F
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1ccc(Br)c(F)c1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 4-bromo-2,3-difluorobenzyl alcohol (175 mg, 0.70 mmol) in dry CH2Cl2 (2 mL) was treated at 0° C. with Et3N (0.14 mL, 1.01 mmol) followed by DMAP (10 mg, 0.08 mmol) and Ms-Cl (0.06 mL, 0.82 mmol). After stirring at 0° C. for 0.5 h and at rt for 1 h, the reaction was quenched with water (2 mL). The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give crude (4-bromo-2,3-difluorophenyl)methyl methanesulfonate as a yellow oil. This material was dissolved in dry DMF (3 mL) and treated with NaN3 (46 mg, 0.71 mmol) at 80° C. until completion of the reaction. The reaction mixture was then cooled down to rt and partitioned between EA and water. The layers were separated and the org. layer dried over MgSO4, filtered and concentrated under reduced pressure to give crude 1-(azidomethyl)-4-bromo-2,3-difluorobenzene as a colorless oil. LC-MS-conditions 07: tR=0.89 min.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][N:3]=[C:2]1[NH:6][C:7]1(O)[C:12](=[CH:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[CH2:11][S:10][CH2:9][C:8]1=[CH:21][C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1>C1(C)C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[CH3:28][C:25]1[CH:26]=[CH:27][C:22]([CH:21]2[N:3]3[CH2:4][CH2:5][S:1][C:2]3=[N:6][C:7]3[C:12](=[CH:13][C:14]4[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=4)[CH2:11][S:10][CH2:9][C:8]2=3)=[CH:23][CH:24]=1
Reactant: Cc1ccc(C=C2CSCC(=Cc3ccc(C)cc3)C2(O)NC2=NCCS2)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1ccc(C=C2CSCC3=C2N=C2SCCN2C3c2ccc(C)cc2)cc1

Procedure:
To a stirred suspension of 4-[(4,5-dihydro-2-thiazolyl)-amino]tetrahydro-3,5-bis[(4-methylphenyl)methylene]thiopyran-4-ol (from Part A) (2.5 gm; 5.9 mmole) in dry toluene (120 ml), is added slowly a solution of titanium tetrachloride (0.56 gm; 3.0 mmole) in toluene (5.4 ml). The orange mixture is heated at reflux temperature for 1.5 hour. After it is cooled, the solid is pulverized and filtered.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][C:10]1([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[O:14][CH2:13][CH2:12][O:11]1>CC(C)=O>[CH2:1]([N:17]1[CH2:18][CH2:19][CH:20]=[C:15]([C:10]2([CH3:9])[O:11][CH2:12][CH2:13][O:14]2)[CH2:16]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: CC1(c2cccnc2)OCCO1
Solvent: CC(C)=O
Product: CC1(C2=CCCN(Cc3ccccc3)C2)OCCO1
Reaction time: 1 h

Procedure:
Benzyl bromide (9.8 ml) was added to a solution of 2-methyl-2-(pyridin-3-yl)-1,3-dioxolane (13.6 g) in acetone (140 ml) and the mixture was refluxed. After confirming the disappearance of the starting material, the acetone was distilled off under reduced pressure. The residue was dissolved in ethanol (140 ml) and while the solution was ice-cooled, sodium borohydride (3.12 g) was gradually added. After the mixture was stirred for 1 hour, water and ethyl acetate were added. The mixture was stirred and, then, allowed to stand. The aqueous layer was separated and extracted with 2 portions of ethyl acetate. The organic layers were combined, washed successively with saturated aqueous sodium hydrogen carbonate solution, water and aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. Finally the solvent was distilled off under reduced pressure to give 2-(1-benzyl-1,2,5,6-tetrahydropyridin-3-yl)-2-methyl-1,3-dioxolane (7.86 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C@H:5]([CH3:16])[NH:6][C:7]1[C:12]([N+:13]([O-])=O)=[CH:11][CH:10]=[CH:9][N:8]=1)[CH3:2]>O1CCCC1.[Pd]>[CH2:1]([O:3][C:4](=[O:17])[C@H:5]([CH3:16])[NH:6][C:7]1[C:12]([NH2:13])=[CH:11][CH:10]=[CH:9][N:8]=1)[CH3:2]
Reactant: CCOC(=O)[C@H](C)Nc1ncccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)[C@H](C)Nc1ncccc1N
Yield: 85 %

Procedure:
A solution of (S)-N-(3-nitro-2-pyridinyl)alanine ethyl ester (5.0 g, 0.0209 mole) in tetrahydrofuran (60 ml) was hydrogenated over 5% palladium on carbon (0.5 g) keeping the temperature of the solution at approximately room temperature to give (S)-N-(3-amino-2-pyridinyl) alanine ethyl ester. The solution of the reduction product was cooled in an ice bath and dried over magnesium sulfate under nitrogen. The solution was filtered and 4-chlorobenzoyl chloride (3.84 g, 0.022 mole) and triethylamine (2.22 g, 0.022 mole) were added simultaneously, dropwise, to the cooled and stirred solution. The reaction mixture was stirred at room temperature overnight under nitrogen and the solvents were removed under reduced pressure. The residue was partitioned between water (50 ml) and ethyl acetate (50 ml). The layers were separated and the aqueous layer was extracted again with ethyl acetate. The combined organic layers were washed twice with water, dried over magnesium sulfate, treated with charcoal, filtered and evaporated to an oil weighing 6.2 g (85% yield). A 2.2-g portion of the oil was dissolved in isopropyl alcohol and the solution was acidified with ethereal hydrogen chloride. The resulting solid was filtered and dried under high vacuum to give 1.70 g of title compound, mp 172°-177° C. with decomposition.