Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[Cs+].[Cs+].[NH:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH:9][C:8]1=O.CI.O>CN(C=O)C>[CH3:8][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH:9][C:1]1=[O:4]
Reactant: O=c1[nH]c2ccccc2[nH]1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(=O)[nH]c2ccccc21
Reaction time: 0.5 h
Yield: 11.6 %

Procedure:
Cesium carbonate (814.5 mg, 2.5 mmol) was added to a stirred solution of benzimidazolinone (335 mg, 2.5 mmol) in DMF (10 mL) under nitrogen at room temperature. After stirring for 30 min., methyl iodide (355 mg, 2.5 mmol) was added and the mixture stirred at room temperature for 18 h. Water was added and the mixture extracted with ethyl acetate. The organic phase was washed with water, dried (magnesium sulfate) and the solvent removed in vacuo. The residue was chromatographed (10-50% ethyl acetate/hexane) to give the title compound (43 mg, 12%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:3]=1[CH:4]=[O:5].Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1c(O)cccc1Cl
Reactant: CCCCCCCCCBr
Product: CCCCCCCCCOc1cccc(Cl)c1C=O

Procedure:
2-chloro-6-hydroxy-benzaldehyde was alkylated with 1-bromononane as in Example 1 to give 2-chloro-6-nonyloxy benzaldehyde. Reduction with sodium borohydroxide as in Example 1 gave 2-chloro-6-nonyloxy benzyl alcohol which on treatment with triphenylphosphine hydrobromide in acetonitrile as in Example 1 yielded [[2-chloro-6-nonyl-oxy]phenyl]methyl]triphenyl phosphonium bromide. Condensation with 7-formyl-3-methyl-2,4,6-octatrienoic acid ethyl ester as described in Example 3 produced (All E)-9-[2-chloro-6-(nonyloxy)phenyl]-3,7-dimethyl-2,4,6,8-nonatetraenoic acid ethyl ester. The ester was subjected to hydrolysis, as in Example 5, to produce (All-E)-9-[2-chloro-6-(nonyloxy)phenyl]-3,7-dimethyl-2,4,6,8-nonatetraenoic acid mp 129-131° (from ethyl acetate/hexane mixture).
Reaction SMILES: [OH-].[K+].[N+:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:14])=[O:13])([O-:5])=[O:4].Br[CH2:23][CH2:24][CH:25]=[CH2:26]>CN(C=O)C.CCOC(C)=O>[CH2:26]([N:15]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[S:12]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[N+:3]([O-:5])=[O:4])(=[O:14])=[O:13])[CH2:25][CH:24]=[CH2:23]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Nc1ccccc1
Reactant: C=CCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCCN(c1ccccc1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 64.7 %

Procedure:
Crushed KOH (0.0484 g, 0.862 mmol, 1.2 equiv) was added to 2-nitro-N-phenylbenzenesulfonamide (0.200 g, 0.719 mmol) in 1 mL DMF, and the mixture was stirred for 30 min. 4-Bromo-1-butene (0.2426 g, 1.80 mmol) in 2 mL DMF solution was added dropwise into the mixture and it was stirred at room temperature overnight. The reaction mixture was diluted with 30 mL EtOAc and washed with 1M HCl 2×10 mL and water 3×10 mL. The organic layer was dried over anhydrous Na2SO4 and evaporated to afford the crude product, which was subjected to silica gel chromatography using Hexanes/EtOAc to afford 0.1546 g white solid, yield 63.5%. 1H NMR (CDCl3, 400 MHz) δppm 2.20 (q, J=6.90 Hz, 2H) 3.83 (t, J=7.15 Hz, 2H) 5.00 (d, J=4.39 Hz, 1H) 5.03 (s, 1H) 5.64-5.83 (m, 1H) 7.14-7.21 (m, 3H) 7.30 (d, J=1.85 Hz, 2H) 7.42-7.46 (m, 2H) 7.52-7.58 (m, 1H) 7.60-7.66 (m, 1H)
Reaction SMILES: [CH2:1]([N:3]([CH2:15][CH3:16])[C:4]([C:6]1[S:10][C:9]([C:11](OC)=[O:12])=[CH:8][CH:7]=1)=[O:5])[CH3:2].O.[NH2:18][NH2:19].O>C(O)C>[CH2:1]([N:3]([CH2:15][CH3:16])[C:4]([C:6]1[S:10][C:9]([C:11]([NH:18][NH2:19])=[O:12])=[CH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: NN
Reactant: CCN(CC)C(=O)c1ccc(C(=O)OC)s1
Solvent: CCO
Solvent: O
Product: CCN(CC)C(=O)c1ccc(C(=O)NN)s1
Yield: 89 %

Procedure:
Methyl 5-(diethylcarbamoyl)thiophene-2-carboxylate (247 mg, 1.02 mmol) in ethanol (9 mL) was stirred with hydrazine monohydrate (495 mg, 10.2 mol) at 90° C. for 6 hours. After addition of water, the reaction solution was extracted with ethyl acetate and chloroform, and the extract was dried over anhydrous magnesium sulfate and concentrated to give the desired product (yield 89%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[N:3]=1.[CH:15]([C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1)=[O:16].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:9]1([CH2:8][C:4]2[N:3]=[C:2]([C:20]3[CH:21]=[CH:22][C:17]([CH:15]=[O:16])=[CH:18][CH:19]=3)[CH:7]=[CH:6][CH:5]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: Brc1cccc(CN2CCCCC2)n1
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=Cc1ccc(-c2cccc(CN3CCCCC3)n2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 87.4 %

Procedure:
To a solution of 2-bromo-6-piperidin-1-ylmethyl-pyridine (example 5) (8.0 g, 31.4 mmol) and 4-formylphenylboronic acid (6.1 g, 40.8 mmol) in toluene/ethanol (4/1, 320 ml) was added an aqueous solution of 2M potassium carbonate. After 15 minutes stirring under a nitrogen atmosphere, tetrakis(triphenylphosphine)palladium(0) (1.2 g, 1.02 mmol) was added. After stirring for 17 h at 80° C. under a nitrogen atmosphere, the mixture was cooled to room temperature and filtered through decalite. Water was added and the product was extracted into ethylacetate. The combined organic phases were washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure. Column chromatography afforded 4-(6-(piperidin-1-ylmethyl)pyridin-2-yl)benzaldehyde (7.69 g) as a white solid.
Reaction SMILES: [CH:1]1([CH2:4][O:5][CH2:6][CH2:7][N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[N:17]2[CH2:23][CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH2:3][CH2:2]1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH:36]=[N:35][N:34]=[N:33]2)=[CH:28][C:27]=1[C:37]([N:39]1[CH2:43][CH2:42][C@:41]([CH2:50][CH2:51]OS(C)(=O)=O)([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:40]1)=[O:38].C(N(CC)CC)C.[I-].[Na+]>C(#N)C>[CH:1]1([CH2:4][O:5][CH2:6][CH2:7][N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[N:17]2[CH2:23][CH2:22][CH2:21][N:20]([CH2:51][CH2:50][C@:41]3([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)[CH2:42][CH2:43][N:39]([C:37]([C:27]4[CH:28]=[C:29]([N:32]5[CH:36]=[N:35][N:34]=[N:33]5)[CH:30]=[CH:31][C:26]=4[O:25][CH3:24])=[O:38])[CH2:40]3)[CH2:19][CH2:18]2)[CH2:2][CH2:3]1
Reactant: c1ccc2c(c1)nc(N1CCCNCC1)n2CCOCC1CC1
Reactant: COc1ccc(-n2cnnn2)cc1C(=O)N1CC[C@](CCOS(C)(=O)=O)(c2ccccc2)C1
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(-n2cnnn2)cc1C(=O)N1CC[C@](CCN2CCCN(c3nc4ccccc4n3CCOCC3CC3)CC2)(c2ccccc2)C1
Temperature: 81 °C
Yield: 70.3 %

Procedure:
Heat at 81° C. a mixture of 1-(2-cyclopropylmethoxy-ethyl)-2-[1,4]diazepan-1-yl-1H-benzoimidazole (0.10 g, 0.33 mmol) and methanesulfonic acid 2-{(S)-1-[1-(2-methoxy-5-tetrazol-1-yl-phenyl)-methanoyl]-3-phenyl-pyrrolidin-3-yl}-ethyl ester (0.60 g, 1.27 mmol, example 47.2), triethylamine (0.136 mL, 3 equivalents), sodium iodide (0.097 g, 2 equivalents) and acetonitrile (8.1 mL) under argon for 30 hours. Quench the reaction as described in Example 113. Purify the crude material by column chromatography (silica gel, 4.5 cm×15 cm, using step gradient elution with 0%, 5% and 10% methanol in dichloromethane. Concentrate the appropriate fractions to afford 0.16 g of the title compound, Rf=0.33 (silica gel, 10% methanol in dichloromethane). The compound may be converted to the dihydrochloride salt, m.p. 135-155° C. (dec.), by methods well known in the art.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:3]=1[CH2:4][C@H:5]1[CH2:10][C@H:9]([C:11](=[O:18])[CH2:12][C:13](OCC)=[O:14])[CH2:8][CH2:7][N:6]1[C:19]([O:21][CH3:22])=[O:20].[OH-].[Na+].[NH2:30]O.Cl>CO.O>[F:1][C:2]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:3]=1[CH2:4][C@H:5]1[CH2:10][C@H:9]([C:11]2[O:18][NH:30][C:13](=[O:14])[CH:12]=2)[CH2:8][CH2:7][N:6]1[C:19]([O:21][CH3:22])=[O:20]
Reactant: CCOC(=O)CC(=O)[C@@H]1CCN(C(=O)OC)[C@@H](Cc2cc(F)ccc2F)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1cc(F)ccc1F
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 98.5 %

Procedure:
Trans-methyl 2-(2,5-difluorobenzyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (0.611 g, 1.59 mmol) (from example 124, step 1) was dissolved in MeOH (5 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (0.064 g, 1.59 mmol) dissolved in water (0.500 mL) was added during 10 min and the colourless solution continued to stir at −40° C. for 20 min. Hydroxylamine (50% by weight in water, 0.098 mL, 1.59 mmol) was added during 8 min. The resulting solution was stirred at −40° C. for 3 h. The mixture was then transferred into a prewarmed (80° C.) solution of 6 M hydrogen chloride (8 mL, 48.00 mmol) and the mixture continued to stir at 80° C. for 20 min. The solvent was evaporated and DCM/water added. The phases were separated and the organic phase passed through a phase separator and evaporated to yield crude trans-methyl 2-(2,5-difluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (0.552 g, 98%) as a yellow semi-solid. MS m/z 353 (M+H)+
Reaction SMILES: [NH2:1][OH:2].Cl.CC(O[Na])=O.[C:9]12[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:15][C:14]1[C:13](=O)[CH2:12][CH2:11][C:10]2=1>CO>[C:9]12[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:15][C:14]1/[C:13](=[N:1]\[OH:2])/[CH2:12][CH2:11][C:10]2=1
Reactant: NO
Reactant: O=C1CCc2c1sc1ccccc21
Agent: CC(=O)O[Na]
Agent: Cl
Solvent: CO
Product: O/N=C1/CCc2c1sc1ccccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92.8 %

Procedure:
To a solution of NH2OH.HCl (18.4 g, 266 mmol) in MeOH (600 mL) at 0° C. was slowly added CH3COONa (21.8 g, 266 mmol). After stirring at 0° C. for 30 min, 329d (10 g, 53 mmol) was added. The reaction solution was allowed to warm to room temperature and stirred for overnight. It was then evaporated in vacuo. 100 mL of water was added to the residue and the resulting mixture was extracted with ethyl acetate (500 mL×3). The organic layers were combined, washed with brine (50 mL), and dried over sodium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure to give 329e as a yellow solid (10 g, 92%). MS: [M+H]+ 203.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[CH2:13][CH2:12][NH:11][CH2:10][C:9]=3[O:14][C:4]=2[CH:3]=1.[CH:15](=O)C>>[I:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[CH2:13][CH2:12][NH:11][CH:10]([CH3:15])[C:9]=3[O:14][C:4]=2[CH:3]=1
Reactant: Ic1ccc2c3c(oc2c1)CNCC3
Reactant: CC=O
Product: CC1NCCc2c1oc1cc(I)ccc21

Procedure:
Synthesized as described for 7-iodo-1,2,3,4-tetrahydro[1]benzofuro[2,3-c]pyridine using acetaldehyde. 1H-NMR (400 MHz, CDCl3): δ 1.60 (d, 3H), 2.92 (m, 2H), 3.37 (m, 1H), 3.59 (m, 1H), 4.77 (m, 1H), 7.46 (d, 1H), 7.64 (dd, 1H), 8.07 (d, 1H), 9.58 (bs, 1H), 10.02 (bs, 1H).
Reaction SMILES: [Br:1][C:2]1[C:3]2[O:11][CH:10]=[CH:9][C:4]=2[C:5](=[O:8])[NH:6][CH:7]=1.[CH3:12]I.[NH4+].[Cl-]>CN(C=O)C>[Br:1][C:2]1[C:3]2[O:11][CH:10]=[CH:9][C:4]=2[C:5](=[O:8])[N:6]([CH3:12])[CH:7]=1
Reactant: CI
Reactant: O=c1[nH]cc(Br)c2occc12
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: Cn1cc(Br)c2occc2c1=O
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a suspension of 7-bromo-5H-furo[3,2-c]pyridin-4-one (250 mg, 1.17 mmol) in DMF (5 mL) cooled to 0° C. was added HNa (56 mg, 1.4 mmol, 60% dispersion in mineral oil) in three portions. After stirring at room temperature for 45 min, MeI (87 μl, 1.4 mmol) was added drop wise over five minutes. The reaction was allowed to warm up to rt stirred for 2 h. It was then cooled to 0° C. followed by addition of sat. aq. NH4Cl (5 mL) drop wise. The resulting mixture was extracted with EtOAc (3×5 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford the title compound. LCMS: 227.9 (M+H)+
Reaction SMILES: [N:1]1([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([C:17]([F:20])([F:19])[F:18])=[N:15][N:16]=3)[N:13]=2)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:21][C:22]([F:32])([F:31])[C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1>>[F:20][C:17]([F:18])([F:19])[C:14]1[N:12]2[N:13]=[C:8]([N:1]3[CH2:7][CH2:6][CH2:5][N:4]([CH2:27][C:26]4[CH:25]=[CH:24][C:23]([C:22]([F:21])([F:31])[F:32])=[CH:30][CH:29]=4)[CH2:3][CH2:2]3)[CH:9]=[CH:10][C:11]2=[N:16][N:15]=1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: FC(F)(F)c1nnc2ccc(N3CCCNCC3)nn12
Product: FC(F)(F)c1ccc(CN2CCCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1

Procedure:
Reductive amination of 6-(1,4-diazepan-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 4-(trifluoromethyl)benzaldehyde was carried out according to General Synthetic Method 8. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile as eluents to give 3-(trifluoromethyl)-6-[4-[[4-(trifluoromethyl)phenyl]methyl]-1,4-diazepan-1-yl]-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:15][CH2:14][S:13][CH2:12][C@H:11]2[C:16]([OH:18])=[O:17])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[C:20]1([CH:26]=[CH:27][CH2:28]O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:20]1([CH:26]=[CH:27][CH2:28][O:17][C:16]([C@@H:11]2[CH2:12][S:13][CH2:14][CH2:15][N:10]2[S:7]([C:4]2[CH:3]=[CH:2][C:1]([CH3:19])=[CH:6][CH:5]=2)(=[O:9])=[O:8])=[O:18])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)N2CCSC[C@H]2C(=O)O)cc1
Reactant: OCC=Cc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N2CCSC[C@H]2C(=O)OCC=Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 50.3 %

Procedure:
0.301 g (1 mmol) of (3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid, 0.200 g (1.5 mmol) of (3-phenyl)-allyl alcohol, 0.088 g (0.33 mmol) of CAS, 0.227 g (1.2 mmol) of DCC and 0.04 g (0.33 mmol) of DMAP were dissolved in 15 mL of CH2Cl2. The mixture was stirred for 24 h at room temperature. The solid was filtrated and the solvent was evaporated. The residual was dissolved in a suitable amount of ethyl acetate (20 ml) and then the mixture was filtered to remove insoluble substance. The ethyl acetate was added to 60 ml and then the liquid was washed with 10% NaHCO3 solution, saturated NaCl solution and dried over Na2SO4. After the drying agent was removed and part of ethyl acetate was evaporated, the crude product was purified by flash column chromatography (eluent: ethyl acetate:cyclohexane=1:4) to obtain the product as a oil (0.21 g).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[Cl:11][C:12]1[CH:17]=[C:16](Cl)[N:15]=[CH:14][N:13]=1.O>CC(N(C)C)=O>[Cl:11][C:12]1[N:13]=[CH:14][N:15]=[C:16]([O:10][C:7]2[CH:6]=[CH:5][C:4]([NH2:3])=[N:9][CH:8]=2)[CH:17]=1
Reactant: Nc1ccc(O)cn1
Reactant: Clc1cc(Cl)ncn1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Nc1ccc(Oc2cc(Cl)ncn2)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.4 %

Procedure:
A −10° C. suspension of NaH (60% in mineral oil, 0.73 g, 18.2 mmol) in DMA (15 mL) was treated with 6-aminopyridin-3-ol (1.0 g, 9.1 mmol), stirred for 0.5 h, treated drop-wise with a solution of 4,6-dichloropyrimidine (2.03 g, 13.6 mmol) in DMA (10 mL), warmed to RT and stirred for 2 h. The mixture was treated with water, extracted with DCM (3×) and the combined organics were washed with 5% LiCl, then brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (EtOAc) to afford 5-((6-chloropyrimidin-4-yl)oxy)pyridin-2-amine (1.0 g, 50%). 1H NMR (400 MHz, DMSO-d6): δ 8.62 (d, 1 H), 7.79 (d, 1 H), 7.33-7.26 (m, 2 H), 6.48 (d, 1 H), 6.00 (s, 2 H); MS (ESI) m/z: 223.0 (M+H+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][C:26]=1[O:27][CH:28]([CH3:30])[CH3:29])[CH2:6][O:7][C:8]1[CH:16]=[CH:15][C:14]2[N:13]3[CH2:17][CH2:18][CH:19]([CH2:20][C:21]([OH:23])=[O:22])[C:12]3=[CH:11][C:10]=2[CH:9]=1)#[N:2].C1C(=O)N([Cl:38])C(=O)C1>C(Cl)Cl>[Cl:38][C:11]1[C:10]2[CH:9]=[C:8]([O:7][CH2:6][C:5]3[CH:24]=[CH:25][C:26]([O:27][CH:28]([CH3:30])[CH3:29])=[C:3]([C:1]#[N:2])[CH:4]=3)[CH:16]=[CH:15][C:14]=2[N:13]2[CH2:17][CH2:18][CH:19]([CH2:20][C:21]([OH:23])=[O:22])[C:12]=12
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)Oc1ccc(COc2ccc3c(c2)cc2n3CCC2CC(=O)O)cc1C#N
Solvent: ClCCl
Product: CC(C)Oc1ccc(COc2ccc3c(c2)c(Cl)c2n3CCC2CC(=O)O)cc1C#N
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 92.1 %

Procedure:
2-(7-(3-Cyano-4-isopropoxybenzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic Acid (50 mg, 0.124 mmol) was dissolved in DCM (1 mL) and cooled to 0° C. NCS (16.51 mg, 0.124 mmol) was added and the reaction was stirred at 0° C. for 15 min in a 20 mL sealed scintillation vial. The mixture was diluted with DCM and washed with water (2×10 mL), Na2S2O3 (aq) (2×10 mL), dried over MgSO4, and filtered by vacuum filtration through a glass fiber paper. The solvent was removed under reduced pressure to give the title compound (50.1 mg) as a yellow solid. LCMS m/z=439.3 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δppm 1.32 (d, J=6.06 Hz, 6H), 2.24-2.35 (m, 1H), 2.52-2.59 (m, 1H), 2.77-2.87 (m, 1H), 2.94 (dd, J=16.29, 4.04 Hz, 1H), 3.64-3.73 (m 1H), 3.96-4.07 (m, 1H), 4.10-4.20 (m, 1H), 4.79 (dt, J=12.09, 6.02 Hz, 1H), 5.07 (s, 2H), 6.86 (dd, J=8.72, 2.40 Hz, 1H), 6.96 (d, J=2.27 Hz, 1H), 7.29 (dd, J=8.84, 3.79 Hz, 2H), 7.72 (dd, J=8.78, 2.21 Hz, 1H), 7.79 (d, J=2.15 Hz, 1H), 12.35 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][NH2:10])[CH:5]=[CH:6][C:7]=1[Cl:8].O[C:12]1[C:13]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([NH2:24])=[O:23])[C:14]=2[N:15]=[N:16][N:17]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[Cl:8])[CH2:9][NH:10][C:12]1[C:13]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([NH2:24])=[O:23])[C:14]=2[N:15]=[N:16][N:17]=1
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: NC(=O)c1cccc2c(O)nnnc12
Product: NC(=O)c1cccc2c(NCc3ccc(Cl)c(Cl)c3)nnnc12

Procedure:
Compound 2 was prepared following general synthetic scheme 7 wherein (3,4-dichlorophenyl)methanamine was reacted with 4-hydroxybenzo[d][1,2,3]-triazine-8-carboxamide to give the title compound. LC-MS [350 (M+1)], 1H NMR (400 MHz, DMSO-d6): δ 9.37 (s, 1H), 9.31 (t, 1H), 8.54 (d, 1H), 8.49 (d, 1H), 8.05 (s, 1H), 8.00 (t, 1H), 7.70 (s, 1H), 7.60 (d, 1H), 7.40 (d, 1H), 4.90 (d, 1H).
Reaction SMILES: O[C:2]1([CH:8]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=2)[C:9]2[N:10]=[N:11][NH:12][CH:13]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.S(Cl)(Cl)=O>ClCCl>[C:2]1(=[C:8]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=2)[C:9]2[N:10]=[N:11][NH:12][CH:13]=2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: N#Cc1ccc(C(c2c[nH]nn2)C2(O)CCCCC2)cc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: N#Cc1ccc(C(=C2CCCCC2)c2c[nH]nn2)cc1
Reaction time: 2 h
Yield: 36.5 %

Procedure:
7.6 g of crude 4-[1-hydroxycyclohex-1-yl-1(1,2,3-triazolyl)methyl]benzonitrile is dissolved at 0° in 50 ml of dichloromethane and stirred at 0° for 1 hour with 22.7 ml of thionyl chloride. Then the mixture is concentrated to dryness under vacuum, dissolved in 50 ml of dichloromethane, stirred with 30 ml of triethylamine for 2 hours, diluted with water, extracted three times with ethyl acetate, washed with water, dried over sodium sulfate, concentrated to dryness under vacuum, and chromatographed on silica gel with hexane/ethyl acetate, thus obtaining 2.6 g of 4-[1-cyclohexylidene-1-(1,2,3-triazolyl) methyl]benzonitrile as the free base, 132°-133° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[C@@H:12]([C@H:13]([OH:15])[CH3:14])[CH2:11][O:10][C:9]2=[O:16])[CH:5]=[C:4]([Cl:17])[N:3]=1.[CH2:18](Cl)Cl.F[B-](F)(F)F.[H+].C[Si](C=[N+]=[N-])(C)C>CCOC(C)=O.CCCCCCC>[Cl:1][C:2]1[N:7]=[C:6]([N:8]2[C@@H:12]([C@H:13]([O:15][CH3:18])[CH3:14])[CH2:11][O:10][C:9]2=[O:16])[CH:5]=[C:4]([Cl:17])[N:3]=1
Reactant: C[C@@H](O)[C@H]1COC(=O)N1c1cc(Cl)nc(Cl)n1
Reactant: ClCCl
Agent: C[Si](C)(C)C=[N+]=[N-]
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CO[C@H](C)[C@H]1COC(=O)N1c1cc(Cl)nc(Cl)n1
Temperature: 0 °C
Yield: 31 %

Procedure:
To a round bottom flask was added (R)-3-(2,6-dichloropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one (364 mg, 1.31 mmol) followed by the addition of DCM (10.8 mL). The reaction mixture was then cooled to 0° C. in a (ice/water bath) under nitrogen. To this cold solution was added tetrafluoroboric acid (0.20 mL, 1.31 mmol, 50% aqueous solution) followed by the addition of trimethylsilyldiazomethane (1.96 mL, 3.93 mmol, 2 M in hexanes) divided into 3 portions added 20 min apart. A second addition of trimethylsilyldiazomethane in hexanes (1.96 mL, 3.93 mmol, 2 M in hexanes) again divided into 3 portions added 20 min apart was added. Reaction mixture was quenched with water and diluted with DCM. Phases paritioned and the aqueous phase extracted with DCM. Organic phases combined and washed with brine, dried (Na2SO4), filtered and concentrated onto silica gel. Silica gel column chromatography (EtOAc/Heptane 0 to 100%) provided (R)-3-(2,6-dichloropyrimidin-4-yl)-4-((R)-1-methoxyethyl)oxazolidin-2-one (119 mg, 0.41 mmol, 31% yield) as a colorless oil which crystallizes upon standing. 1H NMR (400 MHz, CDCl3) δ 1.09 (d, J=6.50 Hz, 3H) 3.44 (s, 3H) 4.09 (qd, J=6.46, 4.16 Hz, 1H) 4.38-4.49 (m, 1H) 4.60 (dd, J=9.49, 2.84 Hz, 1H) 4.99 (ddd, J=8.50, 3.95, 2.96 Hz, 1H) 8.23 (s, 1H). LCMS m/z 292.0 (M+H)+, Rt 0.86 min.
Reaction SMILES: [H-].[Na+].[N+:3]([CH3:6])([O-:5])=[O:4].[O:7]=[C:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][NH:26][C:27](=[O:29])[CH3:28])[O:22][C:21]3=[O:30])=[CH:16][C:15]=2[F:31])[CH2:10][CH2:9]1>>[N+:3]([CH2:6][C:8]1([OH:7])[CH2:9][CH2:10][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][NH:26][C:27](=[O:29])[CH3:28])[O:22][C:21]3=[O:30])=[CH:16][C:15]=2[F:31])[CH2:12][CH2:13]1)([O-:5])=[O:4]
Reactant: C[N+](=O)[O-]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(=O)CC3)c(F)c2)C(=O)O1
Agent: [H-]
Agent: [Na+]
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(O)(C[N+](=O)[O-])CC3)c(F)c2)C(=O)O1
Reaction time: 0.5 h
Yield: 17 %

Procedure:
To a stirred suspension of sodium hydride (0.72 g, 17.0 mmol) in dry tetarhydrofuran (40 ml) was added nitromethane (12.4 mmol) at 0° C. temperature. It was further stirred for 30 minutes and then (S)-N-{3-[4-(4-oxo-piperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (7.2 mmol) was added. The reaction mixture was stirred at 65° C. for 24 hours. The reaction mixture was poured on to crushed ice. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2×20 ml). The removal of solvent afforded a crude compound, which was purified by column chromatography over silica gel to afford title compound in 17% yield. M.P. 186-187° C. and MS (M+1)=384 (MH+, 100%) M.F.=C18H23FN4O6.