Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[F:11].[CH3:13][S:14]([C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Cl)=[CH:19][CH:18]=1)(=[O:16])=[O:15]>>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:21][C:20]2[CH:19]=[CH:18][C:17]([S:14]([CH3:13])(=[O:16])=[O:15])=[CH:24][CH:23]=2)=[CH:6][C:5]=1[F:11]
Reactant: COC(=O)c1ccc(O)cc1F
Reactant: CS(=O)(=O)c1ccc(CCl)cc1
Product: COC(=O)c1ccc(OCc2ccc(S(C)(=O)=O)cc2)cc1F

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure E except KI (1.0 eq.) is also added from 2-fluoro-4-hydroxy-benzoic acid methyl ester [CAS 197507-22-5] and 4-methylsulfonylbenzyl chloride. 1H NMR (DMSO) 8.0 (d, 2H), 7.9 (t, 1H), 7.7 (d, 2H), 7.1 (dd, 1H), 7.0 (dd, 1H), 5.4 (s, 2H), 3.8 (s, 3H), 3.3 (s, 3H)
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([O:12][CH3:13])[CH:6]=2.[C:14]([C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[C:19]([F:26])[CH:18]=1)([OH:16])=[O:15].C([O-])([O-])=O.[K+].[K+]>COCCOCCO.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:26][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][C:20]=1[C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([O:12][CH3:13])[CH:6]=2)[C:14]([OH:16])=[O:15]
Reactant: O=C(O)c1ccc(B(O)O)c(F)c1
Reactant: COc1ccc2cc(Cl)ncc2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOCCO
Solvent: O
Product: COc1ccc2cc(-c3ccc(C(=O)O)cc3F)ncc2c1
Temperature: 120 °C
Reaction time: 3 h
Yield: 30.4 %

Procedure:
A mixture of 3-chloro-7-methoxyisoquinoline (Intermediate 12) (300 mg, 1.55 mmol), 4-carboxy-2-fluorophenylboronic acid (285 mg, 1.55 mmol), K2CO3 (642 mg, 4.65 mmol) and Pd(dppf)Cl2 (30 mg, 0.037 mmol) in DEGME (7 mL) and water (2 mL) was stirred under N2 atmosphere at 120° C. for 3 hours. The resulting mixture was cooled to room temperature and filtered. The filtrate was acidified with aqueous HCl (2M) until pH=6 and filtered. The solid was dried under reduced pressure to give 3-fluoro-4-(7-methoxyisoquinolin-3-yl)benzoic acid (140 mg, yield: 30%) as off-white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[NH:12][C:11]([CH2:13][CH2:14][CH2:15][CH3:16])=[N:10][C:5]2=[N:6][C:7]=1[CH2:8][OH:9].[H][H]>C(O)C.[Pd]>[CH2:13]([C:11]1[NH:12][C:4]2[C:5]([N:10]=1)=[N:6][C:7]([CH2:8][OH:9])=[CH:2][CH:3]=2)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCc1nc2nc(CO)c(Br)cc2[nH]1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCCc1nc2nc(CO)ccc2[nH]1
Yield: 92.5 %

Procedure:
0.25 g(0.00088 mole) of 6-bromo-2-butyl-5-hydroxymethyl-1H-imidazo[4,5-b]pyridine obtained in step 6 of Example 1 was dissolved in 10 ml of ethanol and to the resulting solution was added 0.03 g of 10% palladium/activated carbon. The resultant was reacted at room temperature for 3 hours under about 3 atm of hydrogen using a hydrogenation apparatus. The reaction solution was filtered through Cellite with washing with 10% methanol/ethyl acetate(10 ml×3) and concentrated under reduced pressure to obtain 0.167 g of the title compound(yield 93%).
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)=[O:5].[CH3:16][Mg]Br>C1COCC1.C(OCC)C>[C:11]([N:9]1[CH:10]=[C:6]([C:4](=[O:5])[CH3:16])[CH:7]=[N:8]1)([CH3:14])([CH3:13])[CH3:12]
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)c1cnn(C(C)(C)C)c1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(=O)c1cnn(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Under nitrogen, a solution of 5.87 g (27.7 mmol) 1-tert-butyl-1H-pyrazole-4-carboxylic acid methoxy-methyl-amide in 55 ml THF is cooled to 0° C. and 18.5 ml (55.5 mmol) of a 3 M solution of methylmagnesium bromide in diethyl ether is added dropwise at 0° C. The reaction mixture is stirred for 18 hours at room temperature. The reaction mixture is partitioned between brine and ethyl acetate. The organic phase is dried over sodium sulfate and evaporated. The residue is chromatographed on a silica gel column with cyclohexane/ethyl acetate as eluent to afford 1-(1-tert-butyl-1H-pyrazol-4-yl)-ethanone as white solid; HPLC/MS 1.87 min (B), [M+H] 167;
Reaction SMILES: [CH2:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][C:4](=[O:13])[N:3]3[CH2:2]1.[Cl:14][CH2:15][CH2:16][C:17](Cl)=[O:18]>>[Cl:14][CH2:15][CH2:16][C:17]([C:9]1[CH:8]=[C:7]2[C:12]3=[C:11]([CH2:1][CH2:2][N:3]3[C:4](=[O:13])[CH2:5][CH2:6]2)[CH:10]=1)=[O:18]
Reactant: O=C(Cl)CCCl
Reactant: O=C1CCc2cccc3c2N1CC3
Product: O=C(CCCl)c1cc2c3c(c1)CCN3C(=O)CC2

Procedure:
Using 1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one (10.0 g) and 3-chloropropanoyl chloride (6.06 ml) according to the same method as that of Reference Example 1, the title compound (12.0 g) was obtained as colorless crystals having a melting point of 154 to 155° C.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:19]3=[N:20][S:21](=[O:25])(=[O:24])[CH2:22][CH2:23][N:18]3[CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1.C(O)C.[C].[Rh].[Pt](=O)=O>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([CH:14]2[C:19]3=[N:20][S:21](=[O:25])(=[O:24])[CH2:22][CH2:23][N:18]3[CH2:17][CH2:16][CH2:15]2)=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S1(=O)CCN2C=CC=C(c3ccc(Oc4ccccc4)cc3)C2=N1
Agent: O=[Pt]=O
Agent: [Rh]
Solvent: CCO
Solvent: C1CCOC1
Product: O=S1(=O)CCN2CCCC(c3ccc(Oc4ccccc4)cc3)C2=N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.4 %

Procedure:
A mixture of 9-(4-phenoxyphenyl)-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (173 mg) and 5% rhodium-carbon (50% wet, 17 mg) in THF (50 ml) and ethanol (20 mL) was stirred under a hydrogen atmosphere at room temperature overnight. To the reaction mixture was added platinum dioxide (17 mg), and the mixture was stirred under a hydrogen atmosphere at room temperature for 7 hr. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by aminopropyl silica-bound silica gel column chromatography (ethyl acetate/methanol) to give the title compound (153 mg) as a white solid. The obtained solid was crystallized from acetonitrile and diisopropyl ether.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7](O)=[O:8].FC1C=C(C(O)=O)C=C(C=1)C(O)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:1][C:2]1[CH:10]=[C:6]([CH2:7][OH:8])[CH:5]=[N:4][CH:3]=1
Reactant: Cc1cncc(C(=O)O)c1
Agent: O=C(O)c1cc(F)cc(C(=O)O)c1
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: Cc1cncc(CO)c1
Reaction time: 0.42 h
Yield: 41.6 %

Procedure:
To stirring solution of 233 mg (1.70 mmol) of 5-methylnicotinic acid (synthesized following the general procedure for 5-fluoro-isophthalic acid) in 30 mL of THF at 0° C. was added 181 mg (4.76 mmol) of LiAlH4. After 25 min., the reaction was quenched by adding successively 180 μL of H2O, 180 μL of 15% aqueous NaOH, and 540 μL of brine. The mixture was filtered through Celite and concentrated to give 87 mg of (5-methylpyridin-3-yl)methanol which was used for the next reaction without further purification.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH:6]2[CH2:8][CH2:9][CH:3]1[C:4](=O)[NH:5]2.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH:6]12[CH2:8][CH2:9][CH:3]([CH:2]([OH:1])[CH2:7]1)[CH2:4][NH:5]2
Reactant: O=C1NC2CCC1C(O)C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OC1CC2CCC1CN2

Procedure:
Compound (4) can be reacted with LAH in solvent (such as THF), with reflux under nitrogen to yield 2-aza-bicyclo[2.2.2]octane-5-ol (5).
Reaction SMILES: [C:1]1([S:7][CH2:8][C@H:9]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([S:21](=[O:24])(=[O:23])[NH2:22])=[CH:17][C:16]=2[S:25]([C:28]([F:31])([F:30])[F:29])(=[O:27])=[O:26])[CH2:10][C:11](O)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:32]([N:34]([CH2:37][C@@H:38]1[CH2:43][O:42][CH2:41][CH2:40][N:39]1C(OC(C)(C)C)=O)[CH2:35][CH3:36])[CH3:33].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CC(N(C)C)=O.C(OCC)(=O)C>[CH2:32]([N:34]([CH2:37][C@H:38]1[N:39]([C:11](=[O:12])[CH2:10][C@@H:9]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([NH2:22])(=[O:23])=[O:24])=[CH:17][C:16]=2[S:25]([C:28]([F:29])([F:31])[F:30])(=[O:27])=[O:26])[CH2:8][S:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:40][CH2:41][O:42][CH2:43]1)[CH2:35][CH3:36])[CH3:33]
Reactant: CCN(CC)C[C@@H]1COCCN1C(=O)OC(C)(C)C
Reactant: NS(=O)(=O)c1ccc(N[C@@H](CSc2ccccc2)CC(=O)O)c(S(=O)(=O)C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)C[C@@H]1COCCN1C(=O)C[C@H](CSc1ccccc1)Nc1ccc(S(N)(=O)=O)cc1S(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.6 %

Procedure:
To a solution of (R)-4-(phenylthio)-3-(4-sulfamoyl-2-(trifluoromethylsulfonyl)phenylamino) butanoic acid (INTERMEDIATE 8, 500 mg, 1.00 mmol), (R)—N-ethyl-N-(morpholin-3-ylmethyl)ethanamine hydrochloride salt (INTERMEDIATE 90, 209 mg, 1.00 mmol), DIPEA (0.701 ml, 4.01 mmol) in DMA (5 ml) was added HATU (458 mg, 1.20 mmol). The mixture was stirred for 1 h at room temperature and diluted with ethyl acetate (200 ml). The mixture was washed successively with 1M aq. sodium bisulfate, saturated sodium bicarbonate, and brine. The organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified column chromatography (ISCO, eluting with 0→100% DCM/10% 2 M ammonia in MeOH in DCM over 24 minutes) to give the title product (200 mg, yield: 30.5%).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)S([O:12][CH2:13][C:14]([F:17])([F:16])[F:15])(=O)=O.[CH3:20][C:21]1[N:22]=[CH:23][N:24]([C:26]2[C:27](O)=[N:28][C:29](/[CH:32]=[CH:33]/[C:34]3[N:52]=[C:37]4[C@H:38]([C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=5[C:48]([F:51])([F:50])[F:49])[CH2:39][CH2:40][CH2:41][N:36]4[N:35]=3)=[CH:30][CH:31]=2)[CH:25]=1.CN(C=O)C>C(OCC)(=O)C.O>[CH3:20][C:21]1[N:22]=[CH:23][N:24]([C:26]2[CH:31]=[CH:30][C:29](/[CH:32]=[CH:33]/[C:34]3[N:52]=[C:37]4[CH:38]([C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=5[C:48]([F:50])([F:51])[F:49])[CH2:39][CH2:40][CH2:41][N:36]4[N:35]=3)=[N:28][C:27]=2[O:12][CH2:13][C:14]([F:15])([F:16])[F:17])[CH:25]=1
Reactant: Cc1cn(-c2ccc(/C=C/c3nc4n(n3)CCC[C@H]4c3ccccc3C(F)(F)F)nc2O)cn1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cn(-c2ccc(/C=C/c3nc4n(n3)CCCC4c3ccccc3C(F)(F)F)nc2OCC(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Cesium carbonate (83.7 mg) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (35.7 μL) were added to a mixture of 3-(4-methyl-1H-imidazol-1-yl)-6-{(E)-2-[8-(2-trifluoromethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]vinyl}pyridin-2-ol synthesized in Example 344 (100 mg) and DMF (1.2 mL), and the reaction solution was stirred at room temperature for four hours. Water and ethyl acetate were added to the reaction solution, and the organic layer was separated. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (carrier: Chromatorex NH; elution solvent: heptane:ethyl acetate=4:1→ethyl acetate) to obtain a racemate of the title compound (110 mg). The resulting racemate (110 mg) was separated by CHIRALPAK™ IB manufactured by Daicel Chemical Industries, Ltd. (2 cm×25 cm, mobile phase: hexane:ethanol=5:5, flow rate: 11 mL/min) to obtain the title optically active compound with a retention time of 13 minutes and positive optical rotation (51 mg) and the title optically active compound with a retention time of 18 minutes and negative optical rotation (53 mg).
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:17]=[CH:16][S:15][C:5]=3[C:6](=[O:14])[NH:7][C:8]=2[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].[Cl:18][C:19]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[CH:31][C:20]=1[CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27]>>[Cl:18][C:19]1[CH:34]=[C:33]([C:2]2[C:3]3[C:4]4[CH:17]=[CH:16][S:15][C:5]=4[C:6](=[O:14])[NH:7][C:8]=3[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH:32]=[CH:31][C:20]=1[CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27]
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Reactant: CC(C)(C)OC(=O)NCCc1ccc(B2OC(C)(C)C(C)(C)O2)cc1Cl
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(CCNC(=O)OC(C)(C)C)c(Cl)c1
Yield: 56.3 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-one (3.0 g, 9.7 mmol) was reacted with tert-butyl 2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenethylcarbamate (5.53 g, 14.5 mmol) to afford the desired product (2.65 g, 57%) as a light brown solid. ESI MS m/z 485 [C25H25ClN2O4S+H]+.
Reaction SMILES: [N+:1]([C:4]1[C:5](O)=[N:6][CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)([O-:3])=[O:2].O(Br)[Br:16].[P+5]>C(#N)C>[Br:16][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][C:8]([C:10]([F:13])([F:12])[F:11])=[CH:7][N:6]=1
Reactant: BrOBr
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cnc1O
Agent: [P+5]
Solvent: CC#N
Product: O=[N+]([O-])c1cc(C(F)(F)F)cnc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Nitro-5-(trifluoromethyl)pyridin-2-ol (31.00 g, 149 mmol) was dissolved in acetonitrile (250 ml) to give a dark brown solution. Phosphorus(V) oxybromide (85 g, 298 mmol) was added and the mixture was heated at reflux for 4.5 hours and then stirred at RT overnight. The reaction mixture was quenched by pouring into vigorously stirring water (600 ml) containing sodium hydrogencarbonate (110 g). The dark brown mixture was extracted with DCM (3×200 ml) and the organic phase was washed with water (200 ml) and brine (100 ml), dried (MgSO4) and concentrated in vacuo to afford the title product as a brown oil. 1H-NMR: [400 MHz, CDCl3, δH 8.87 (1H, d, J=1.4 Hz, ArH), 8.39 (1H, d, J=1.9 Hz, ArH).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:30]=[CH:31][CH:32]=1)[CH2:6][N:7]1[CH2:11][CH2:10][C@H:9]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:18]([F:28])[CH:17]=2)(=[O:15])=[O:14])[C:8]1=[O:29])#[N:2].[CH3:33]I>>[C:1]([C:3]1[CH:4]=[C:5]([CH:30]=[CH:31][CH:32]=1)[CH2:6][N:7]1[CH2:11][CH2:10][C@H:9]([N:12]([CH3:33])[S:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:18]([F:28])[CH:17]=2)(=[O:15])=[O:14])[C:8]1=[O:29])#[N:2]
Reactant: N#Cc1cccc(CN2CC[C@H](NS(=O)(=O)c3ccc(-c4ccccc4)c(F)c3)C2=O)c1
Reactant: CI
Product: CN([C@H]1CCN(Cc2cccc(C#N)c2)C1=O)S(=O)(=O)c1ccc(-c2ccccc2)c(F)c1

Procedure:
The title compound is prepared as described in EXAMPLE 26, Part A using 2-fluorobiphenyl-4-sulfonic acid [1-(3-cyanobenzyl)-2-oxopyrrolidin-3-(S)-yl]amide and methyl iodide. The crude product is purified by column chromatography eluting with gradient of 10% EtOAc/CH2Cl2 to 20% EtOAc/CH2Cl2 to afford the title compound as a white foam.
Reaction SMILES: [NH2:1]/[C:2](/[C:6]([CH3:9])([CH3:8])[CH3:7])=[CH:3]\[C:4]#[N:5].O.O.O.O.O.O.O.O.O.O.[S-2:20].[Na+].[Na+].C(OCC)(=O)C>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C1C=CC=CC=1.O>[NH2:1]/[C:2](/[C:6]([CH3:9])([CH3:8])[CH3:7])=[CH:3]\[C:4](=[S:20])[NH2:5]
Reactant: [S-2]
Reactant: CC(C)(C)/C(N)=C/C#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)/C(N)=C/C(N)=S
Yield: 23 %

Procedure:
(Z)-3-amino-4,4-dimethyl-pent-2-enenitrile (26 g, 209.35 mmol), sodium sulfide decahydrate (5.71 g, 73.27 mmol) and tetrabutyl ammonium chloride (9.31 g, 33.49 mmol) in benzene and water (215 mL, 2.5:1, v/v) is stirred at 75° C. under hydrogen sulfide gas for three days. 200 mL of ethyl acetate is added and the layers separated. The organic layer is washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound. Yield 23% over three steps. ESI m/z 159=MH+
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:10][CH2:11][CH2:12][C:13]([OH:20])([CH2:17][CH:18]=[CH2:19])[CH:14]([CH3:16])[CH3:15])[CH3:9])=[CH:4][CH:3]=1.Cl[C:22](Cl)([O:24]C(=O)OC(Cl)(Cl)Cl)Cl.O>C(Cl)Cl>[CH2:17]([C:13]1([CH:14]([CH3:15])[CH3:16])[O:20][C:22](=[O:24])[N:10]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)[CH3:9])[CH2:11][CH2:12]1)[CH:18]=[CH2:19]
Reactant: C=CCC(O)(CCNC(C)c1ccc(Br)cc1)C(C)C
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: C=CCC1(C(C)C)CCN(C(C)c2ccc(Br)cc2)C(=O)O1
Temperature: 25 °C
Yield: 21.1 %

Procedure:
To a solution of 3-{2-[1-(4-bromo-phenyl)-ethylamino]-ethyl}-2-methyl-hex-5-en-3-ol (2.2 g, crude) and TEA (4 eq) in dried CH2Cl2 (60 mL) at 0° C. was added triphosgene (2.12 g, 7.12 mmol). The mixture was stirred at rt till the reaction was over. Water was added, and the layers were separated. The aqueous layer was extracted with CH2Cl2. The combined organic phase was washed with water, dried over Na2SO4, and condensed to give the crude product, which was purified by column to give 6-allyl-3-[1-(4-bromo-phenyl)-ethyl]-6-isopropyl-[1,3]oxazinan-2-one (500 mg, crude).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:16])=[C:4]([CH2:11][CH:12]([OH:15])CO)[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.I([O-])(=O)(=O)=O.[Na+].[BH4-].[Na+].Cl>O.O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([CH2:11][CH2:12][OH:15])[C:3]=1[OH:16]
Reactant: O=[N+]([O-])c1cc(Cl)c(O)c(CC(O)CO)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1cc(Cl)c(O)c(CCO)c1
Temperature: 10 °C
Reaction time: 3 h
Yield: 70 %

Procedure:
To a mixture of 3-(3-chloro-2-hydroxy-5-nitrophenyl)propane-1,2-diol (18.7 g), tetrahydrofuran (300 mL), and water (150 mL) was added sodium periodate (19.3 g) under ice-cooling, followed by stirring for 3 hours under ice-cooling. To this mixture was carefully added sodium borohydride (5.70 g) under ice cooling while maintaining the internal temperature at 10° C. or lower, followed by stirring for 1 hour. To this mixture was added sodium borohydride (2.85 g), followed by stirring for 30 minutes, and then acidified under ice cooling by the slow addition of 1 M hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, then the insoluble materials were separated by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0 to 60:40) to obtain 2-chloro-6-(2-hydroxyethyl)-4-nitrophenol (11.5 g) as a yellow solid.
Reaction SMILES: [C:1]1(=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][NH:2]1.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[SH:22]>>[NH2:2][CH2:1][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]1[S:22][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=1
Reactant: O=C1CCCCCCCCCCCN1
Reactant: Nc1ccccc1S
Product: NCCCCCCCCCCCc1nc2ccccc2s1

Procedure:
In the manner of Example 5, 2-azacylotridecanone was reacted with o-aminothiophenol to yield 2-(11-aminoundecyl)benzothiazole.
Reaction SMILES: C[O:2][C:3](=O)[C:4]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)=[CH:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1.[NH2:20][NH2:21]>C(O)C>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([CH:4]2[CH:5]([C:6]3[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=3)[NH:21][NH:20][C:3]2=[O:2])=[CH:13][CH:14]=1
Reactant: COC(=O)C(=Cc1ccncc1)c1ccc(Cl)cc1
Reactant: NN
Solvent: CCO
Product: O=C1NNC(c2ccncc2)C1c1ccc(Cl)cc1
Temperature: 50 °C

Procedure:
To a solution of 2-(4-Chloro-phenyl)-3-pyridin-4-yl-acrylic acid methyl ester 2.02 g in ethyl alcohol 25 mL was added hydrazine 2.37 g. The reaction was heated to 50° C. for 135 minutes. All solvent was removed after under reduced pressure to afford the title compound as light yellow solid. MS (ES+): 274 (M+H)+.
Reaction SMILES: [CH3:1][C@:2]1([CH2:10][N:11]2[C:15]3[CH:16]=[C:17]([C:20]#[N:21])[CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)CCC[C@:4]2(OC2)[CH2:3]1.[CH3:22][C:23]([C:26]1[O:30][N:29]=[C:28]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH:27]=1)([CH3:25])[CH3:24].CC(C)([O-])C.[K+]>CN1C(=O)CCC1>[CH3:25][C:23]([C:26]1[O:30][N:29]=[C:28]([N:31]2[CH2:35][C@@:34]3([CH2:37][CH2:4][CH2:3][C@@:2]([CH2:10][N:11]4[C:15]5[CH:16]=[C:17]([C:20]#[N:21])[CH:18]=[CH:19][C:14]=5[N:13]=[CH:12]4)([CH3:1])[CH2:36]3)[O:33][C:32]2=[O:38])[CH:27]=1)([CH3:22])[CH3:24]
Reactant: C[C@]1(Cn2cnc3ccc(C#N)cc32)CCC[C@@]2(CO2)C1
Reactant: CC(C)(C)OC(=O)Nc1cc(C(C)(C)C)on1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CC(C)(C)c1cc(N2C[C@@]3(CCC[C@](C)(Cn4cnc5ccc(C#N)cc54)C3)OC2=O)no1
Temperature: 125 °C
Yield: 17.6 %

Procedure:
1-{[(3S,5S)-5-methyl-1-oxaspiro[2.5]oct-5-yl]methyl}-1H-benzimidazole-6-carbonitrile (150 mg, 0.533 mmol), 1,1-dimethylethyl [5-(1,1-dimethylethyl)-3-isoxazolyl]carbamate (320 mg, 1.333 mmol) and potassium tert-butoxide (78 mg, 0.693 mmol) were added to a 10 mL microwave vial while nitrogen purging. Then, NMP (3 mL) was added and the vial was capped and heated to 125° C. for 16 h. The reaction was filtered and purified to give 42 mg (13.3%) of 1-({(5S,7S)-3-[5-(1,1-dimethylethyl)-3-isoxazolyl]-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]dec-7-yl}methyl)-1H-benzimidazole-6-carbonitrile. 1H NMR (400 MHz, MeOH-d4) δ 8.43 (br. s., 1H), 8.19 (s, 1H), 7.82 (d, J=8.28 Hz, 1H), 7.58 (d, J=8.28 Hz, 1H), 6.56 (s, 1H), 4.19 (s, 2H), 3.66-3.79 (m, 2H), 2.04 (d, J=5.77 Hz, 1H), 1.95 (d, J=14.05 Hz, 1H), 1.78-1.90 (m, 1H), 1.65-1.78 (m, 2H), 1.40-1.63 (m, 3H), 1.32 (s, 9H), 1.18 (s, 3H). MS (m/z) 448.3 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C@@H:4]([NH2:12])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C(N(CC)C(C)C)(C)C.C([O:25][C:26](=O)/[CH:27]=[C:28](/[O:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=1)\[CH2:29]Br)C>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C@@H:4]([N:12]1[CH2:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=2)=[CH:27][C:26]1=[O:25])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)[C@@H](N)CC1CCCCC1
Reactant: CCOC(=O)/C=C(\CBr)Oc1cccc(OC)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CC1CCCCC1)N1CC(Oc2cccc(OC)c2)=CC1=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 50 %

Procedure:
To a stirred solution of (S)-2-amino-3-cyclohexyl-propionic acid methyl ester (1.20 g, 0.006 mol) in N,N-dimethylformamide (10 mL) was added N,N-diisopropylethylamine (4.06 g, 0.031 mol) slowly at room temperature, under nitrogen. The resulting mixture was stirred for 5 min and then treated with (E)-4-bromo-3-(3-methoxy-phenoxy)-but-2-enoic acid ethyl ester (2.00 g, 0.006 mol) and the reaction mixture was heated at 110° C.-120° C. for 16 h. After this time, ice water was added and the resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. Purification by flash column chromatography (silica gel (100-200 mesh)) afforded (S)-3-cyclohexyl-2-[4-(3-methoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid methyl ester (1.12 g, 46%) as a yellow oil.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]([C:13]([OH:15])=O)[CH:10]=[N:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:16][C:17]1[NH:21][N:20]=[N:19][N:18]=1>O1CCCC1.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C>[N:1]1([C:7]2[N:12]=[C:11]([C:13]([NH:16][C:17]3[NH:21][N:20]=[N:19][N:18]=3)=[O:15])[CH:10]=[N:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Nc1nnn[nH]1
Reactant: O=C(O)c1cncc(N2CCCCC2)n1
Agent: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1nnn[nH]1)c1cncc(N2CCCCC2)n1

Procedure:
To a suspension fo 1.28 g of 6-(1-piperidinyl) pyrazine-2-carboxylic acid in 18 ml of tetrahydrofuran, 0.95 ml of triethylamine and 0.84 ml of pivaloyl chloride were added dropwise successively at 0 ° C. under stirring. After stirring for 1 hour at 0 ° C., 0.58 g of 5-amino-1H-tetrazole was added to the mixture, and the reaction mixture was stirred for 30 minutes at room temperature, and then refluxed for 12 hours. The reaction mixture was evaporated, and water was added to the residue. The precipitate was collected by filtration, and recrystalized from a mixture of dimethylsulfoxide and methanol affording 0.55 g of the desired compound as yellow columns. The obtained crystal was consistent with that of (a).