Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C@@H:4]1[CH2:9][CH2:8][C@@H:7]([CH3:10])[CH2:6][C@H:5]1[CH:11]=[O:12])([CH3:3])[CH3:2].[C:13]1([CH2:19][CH2:20][CH2:21][Mg]Br)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH:1]([C@@H:4]1[CH2:9][CH2:8][C@@H:7]([CH3:10])[CH2:6][C@H:5]1[C:11](=[O:12])[CH2:21][CH2:20][CH2:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH3:3])[CH3:2]
Reactant: Br[Mg]CCCc1ccccc1
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1C=O
Product: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1C(=O)CCCc1ccccc1

Procedure:
The title compound was prepared following the general procedure of Example 1 starting from (1R,2S,5R)-2-isopropyl-5-methylcyclohexanecarbaldehyde and (3-phenylpropyl)magnesium bromide.
Reaction SMILES: I[CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][P:13](=[O:20])([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16].[N-:21]=[N+:22]=[N-:23].[Na+]>CN(C=O)C>[N:21]([CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][P:13](=[O:20])([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16])=[N+:22]=[N-:23]
Reactant: CCOP(=O)(CCOCCOCCOCCI)OCC
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOP(=O)(CCOCCOCCOCCN=[N+]=[N-])OCC
Temperature: 50 °C

Procedure:
To a solution of diethyl 2-(2-(2-(2-iodoethoxy)ethoxy)ethoxy)ethylphosphonate (1 eq) in DMF (0.5 M) was added sodium azide (3 eq). The reaction mixture was heated at 50° C. overnight. The mixture was then concentrated en vaccuo. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-5% MeOH/DCM to give the product as a colorless oil.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH:13]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)=[CH:16][CH:15]=2)[CH2:12][C:11]([C:26]([C:32]([F:35])([F:34])[F:33])([C:28]([F:31])([F:30])[F:29])[OH:27])=[N:10]1.C(N(CC)CC)C.[CH3:43][S:44](Cl)(=[O:46])=[O:45]>ClCCl>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH:13]([C:14]2[CH:15]=[CH:16][C:17]([N:20]3[CH2:25][CH2:24][N:23]([S:44]([CH3:43])(=[O:46])=[O:45])[CH2:22][CH2:21]3)=[CH:18][CH:19]=2)[CH2:12][C:11]([C:26]([C:28]([F:31])([F:30])[F:29])([C:32]([F:33])([F:35])[F:34])[OH:27])=[N:10]1
Reactant: OC(C1=NN(c2ccccc2Cl)C(c2ccc(N3CCNCC3)cc2)C1)(C(F)(F)F)C(F)(F)F
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CCN(c2ccc(C3CC(C(O)(C(F)(F)F)C(F)(F)F)=NN3c3ccccc3Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.7 %

Procedure:
1-(2-Chloro-phenyl)-5-[4-(piperazin-1-yl)-phenyl]-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole hydrochloride (30.0 mg, 0.06 mmol) prepared in Step 1, triethylamine (42.3 uL, 0.30 mmol) and methanesulfonyl chloride (10.4 mg, 0.09 mmol) were added to dichloromethane (1.0 mL). The reaction mixture was stirred at room temperature for 1 hour, washed with distilled water, 1N hydrochloride, a saturated solution of sodium hydrogen carbonate, and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1) to give 15.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [CH3:1][NH:2][S:3]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:10]([C:22]#[C:23][Si](C)(C)C)[CH:9]=1)(=[O:5])=[O:4].[OH-].[K+].Cl.CCCCCCC>C(O)C.O>[CH3:1][NH:2][S:3]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:10]([C:22]#[CH:23])[CH:9]=1)(=[O:4])=[O:5]
Reactant: CNS(=O)(=O)CCc1ccc(NCc2ccccc2)c(C#C[Si](C)(C)C)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CCCCCCC
Product: C#Cc1cc(CCS(=O)(=O)NC)ccc1NCc1ccccc1
Temperature: 17.5 °C
Reaction time: 2.5 h

Procedure:
2-(4-benzylamino-3-trimethylsilanylethynyl-phenyl)-ethanesulfonic acid methylamide (100 g) was dissolved in ethanol (1000 ml) at 25° C. and cooled to 15-20° C. Potassium hydroxide (20 g) was added slowly maintaining temperature below 25° C., stirred for 2-3 hours and cooled to 10-15° C. pH of the reaction mixture was adjusted to 5 with 10% dilute HCl and concentrated under vacuum below 40° C. to obtain a residue. The residue was dissolved in water (300 ml) and extracted with dichloromethane (2500 ml). The organic layer was washed with water and concentrated under vacuum to obtain a residue. The residue was treated with heptane (400 ml) to obtain a solid which was filtered and dried under vacuum at 50-55° C. for 12 hours. (Yield: 75 g, HPLC Purity: 98%)
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:18][C:19]([O:21]C(C)(C)C)=[O:20]>CC#N>[NH:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([O:1][CH2:18][C:19]([OH:21])=[O:20])[CH:10]=2)[CH:6]=[CH:7]1
Reactant: Oc1ccc2cc[nH]c2c1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(O)COc1ccc2cc[nH]c2c1
Reaction time: 20 h

Procedure:
6-Hydroxyindole (1.0 g, 7.51 mmol) in degassed MeCN (10 mL) was added K2CO3 (1.14 g, 8.26 mmol) followed by tert-butyl bromoacetate (1.16 g, 8.26 mmol) and the reaction mixture was stirred for 20 hours under N2. The precipitate was filtered off and the solvent was removed in vacuo to give (1-H-indole-6-yloxy)-acetic acid. This was converted to [1-Cyclopropylmethyl-3-(thiazol-2-ylcarbamoyl)-1H-indol-6-yloxy]-acetic acid tert-butyl ester following general procedure (A). [1-Cyclopropylmethyl-3-(thiazol-2-ylcarbamoyl)-1H-indol-6-yloxy]-acetic acid was obtained by treating the intermediate with TFA-DCM (1:1) (2 mL) for 90 min before the solvent was removed in vacuo.
Reaction SMILES: O[CH:2]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:3][O:4][C:5]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:6]=1[OH:12]>C1(C)C=CC=CC=1>[C:13]1([CH:2]2[O:12][C:6]3[CH:7]=[CH:8][C:9]([OH:11])=[CH:10][C:5]=3[O:4][CH2:3]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Oc1ccc(O)c(OCC(O)c2ccccc2)c1
Solvent: Cc1ccccc1
Product: Oc1ccc2c(c1)OCC(c1ccccc1)O2

Procedure:
A solution of 2-(2-hydroxy-2-phenylethoxy)benzene-1,4-diol (1.2 g) in toluene (75 ml) was heated with Amberlyst 15 catalyst (0.5 g) under reflux for 7 hrs. After filtering the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (toluene/ethyl acetate/acetic acid=8:1:1). The yield of 2,3-dihydro-2-phenyl-benzo[1,4]dioxin-6-ol is 0.5 g. 1H NMR (DMSO-d6) δ=4.02 (dd, J=8.5, 11.4 Hz, 1H), 4.35 (dd, J=2.3, 11.4 Hz, 1H), 5.11 (dd, J=8.5, 2.3 Hz, 1H), 6.29 (dd, J=2.8, 8.5 Hz, 1H), 6.32 (d, J=2.8 Hz, 1H), 6.75 (d, J=8.5 Hz, 1H), 7.36-7.47 (m, 5H), 8.99 (s, 1H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13](=[O:21])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([NH2:20])[CH:15]=1>O1CCCC1>[CH3:7][N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[CH:13]([OH:21])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([NH2:20])[CH:15]=1
Reactant: Cn1cccc1C(=O)c1cccc(N)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cn1cccc1C(O)c1cccc(N)c1
Temperature: 0 °C

Procedure:
To a stirred suspension of 2 g (50 mmol) of lithium aluminum hydride in 100 ml of anhydrous tetrahydrofuran was added dropwise, at room temperature and under nitrogen atmosphere, a solution of 9 g (45 mmol) of 1-methyl-2-(3'-aminobenzoyl)pyrrole in 100 ml of anhydrous tetrahydrofuran. The reaction mixture was refluxed for 15 minutes, cooled to 0° C. and the excess reagent destroyed by carefully adding ethyl acetate, saturated sodium sulfate solution and solid anhydrous sodium sulfate. The insoluble material was separated by filtration and the filtrate evaporated in vacuo. The unstable 1-methyl-2-(3'-amino-α-hydroxybenzyl)pyrrole thus obtained (9 g, 45 mmol) was dissolved in 150 ml of methanol, cooled to 0° C. and treated with 24 ml (419 mmol) of glacial acetic acid and 5.67 g (90 mmol) of sodium cyanoborohydride. The reaction mixture was stirred at room temperature for 18 hours, poured into 500 ml of saturated sodium carbonate solution and the product extracted with ethyl acetate (3×500 ml). The combined extracts were washed with water (3×300 ml), dried and evaporated in vacuo. The residue was purified by column chromatography on 600 g of silica gel, using hexane-ethyl acetate (80:20) as eluant, obtaining 4.89 g (67%) of the title compound, 1-methyl-2-(3'-aminobenzyl)pyrrole, which was recrystallized from acetone-hexane.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:11](I)=[CH:10][N:9]([CH2:13][C:14]3[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[C:17]([CH3:23])=[CH:16][N:15]=3)[C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1.[C:24]([OH:30])(=[O:29])[CH2:25][CH2:26][C:27]#[CH:28]>>[NH2:8][C:6]1[N:7]=[C:2]([Cl:1])[C:3]2[C:11]([C:28]#[C:27][CH2:26][CH2:25][C:24]([OH:30])=[O:29])=[CH:10][N:9]([CH2:13][C:14]3[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[C:17]([CH3:23])=[CH:16][N:15]=3)[C:4]=2[N:5]=1
Reactant: COc1c(C)cnc(Cn2cc(I)c3c(Cl)nc(N)nc32)c1C
Reactant: C#CCCC(=O)O
Product: COc1c(C)cnc(Cn2cc(C#CCCC(=O)O)c3c(Cl)nc(N)nc32)c1C

Procedure:
The title compound was prepared by Sonogashira coupling of 4-Chloro-5-iodo-7-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine (see Example 1) with 4-pentynoic acid according to the General Procedure A. tR=4.73 min. 1H NMR (DMSO-d6) δ 12.2 (s, 1H), 8.15 (s, 1H), 7.28 (s, 1H), 6.80 (s, 2H), 5.33 (s, 2H), 3.73 (s, 3H), 3.31 (br. s, 2H), 2362 (br. t, 2H), 2.27 (s, 3H), 2.17 (s, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30](Cl)=[O:31])[C@H:13]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:15]=2)=[C:7]([O:33][CH2:34][CH3:35])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:36][O:37][CH2:38][C:39]([N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)=[O:40]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30]([N:44]3[CH2:43][CH2:42][N:41]([C:39](=[O:40])[CH2:38][O:37][CH3:36])[CH2:46][CH2:45]3)=[O:31])[C@H:13]([C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)[C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:15]=2)=[C:7]([O:33][CH2:34][CH3:35])[CH:6]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: COCC(=O)N1CCNCC1
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(C(=O)COC)CC1

Procedure:
1-{4-[(4S,5R)-2-(4-tert-Butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-2-methoxy-ethanone was prepared from (4S,5R)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 11) and 2-methoxy-1-piperazin-1-yl-ethanone in an analogous manner as described in example 25. LR-MS: 651.4 [(M+H)]
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[O:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH:13]([NH2:17])[CH:14]([CH3:16])[CH3:15])[CH2:8][CH2:7]1.[CH3:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1.C([O-])(O)=O.[Na+].Cl>ClCCl.C(OCC)(=O)C.C(N(CC)CC)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[O:5][CH:6]1[CH2:7][CH2:8][N:9]([CH2:12][CH:13]([NH:17][C:27](=[O:28])[C:26]2[CH:30]=[CH:31][C:23]([CH3:22])=[CH:24][CH:25]=2)[CH:14]([CH3:15])[CH3:16])[CH2:10][CH2:11]1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: CC(C)C(N)CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)NC(CN2CCC(Oc3ccc(Cl)c(Cl)c3)CC2)C(C)C)cc1
Reaction time: 2 h

Procedure:
The product of step (iii) (0.2 g) was dissolved in dichloromethane (5 ml), triethylamine (0.126 ml) and 4-methylbenzoyl chloride (0.097 ml) were added. After 2 hours at room temperature, ethyl acetate and aqueous NaHCO3 solution were added, the organic phase separated and the solvent removed to leave an oil. Purification by reverse phase HPLC (with a gradient eluent system (25% MeCN/NH4OAcaq (0.1%) to 95% MeCN//NH4OAcaq (0.1%)) gave a gum. Addition of 1.0M ethereal hydrogen chloride solution gave the titled product as a solid (0.104 g).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:27][CH2:26][C:15]2=[CH:16][CH:17]=[C:18]3[C:22]([C:21](=[O:23])[C:20]([F:25])([F:24])[CH2:19]3)=[C:14]2[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>C(O)C.O>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][C:14]2[C:22]3[CH:21]([OH:23])[C:20]([F:24])([F:25])[CH2:19][C:18]=3[CH:17]=[CH:16][C:15]=2[CH2:26][CH2:27]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)N1CCc2ccc3c(c2CC1)C(=O)C(F)(F)C3
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C(OCc1ccccc1)N1CCc2ccc3c(c2CC1)C(O)C(F)(F)C3
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.1 %

Procedure:
To a stirred solution of the product from step (b) (0.18 g, 0.49 mmol) dissolved in ethanol (2 ml) was added NaBH4 (0.046, 1.21 mmol). The reaction mixture was allowed to stir at RT for 1 hour. The reaction mixture was diluted with water and extracted with DCM (3×). The combined DCM extracts were washed with brine, dried (Na2SO4), and solvent evaporated in vacuo to give the sub-titled compound as a white semi-solid (0.13 g) which was used as obtained in the next step. MS: ESI (positive): 374 (M+H).
Reaction SMILES: [N+:1]([C:4]1[O:8][C:7]([CH:9]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:11][CH:12]([Cl:16])C(Cl)=O.C(N(CC)CC)C>C1C=CC=CC=1>[Cl:11][C:12]([Cl:16])=[CH:9][C:7]1[O:8][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: O=C(Cl)C(Cl)Cl
Reactant: O=Cc1ccc([N+](=O)[O-])o1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: O=[N+]([O-])c1ccc(C=C(Cl)Cl)o1
Reaction time: 0.5 h

Procedure:
To a stirred mixture of 14.1 g of 5-nitro-2-furaldehyde and 22.1 g of dichloroacetyl chloride in 300 ml of benzene was added dropwise at 25°-30° over a 30-minute period a solution of 15.2 g of triethylamine in 50 ml of benzene. The mixture then was stirred at 25°-30° for an additional 30 minutes and then for 90 minutes at reflux. After cooling, the mixture was filtered and the filtrate was washed and dried, concentrated under reduced pressure and Claisen distilled to give a liquid product, b.p.: 88°-98° at 0.3 torr. (mainly 90°-95°). This material was crystallized from acetone/petroleum ether to give 1 as a light yellow solid, m.p.: 74°-75°.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C:13]2([CH2:31][OH:32])[O:18][C:17]3[CH:19]=[CH:20][C:21]([N+:23]([O-:25])=[O:24])=[CH:22][C:16]=3[N:15]3[C:26](=[O:30])[N:27]([CH3:29])[N:28]=[C:14]23)(=O)=O)=CC=1.C([Li])CCC>C1COCC1>[CH3:29][N:27]1[C:26](=[O:30])[N:15]2[C:16]3[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:17]=3[O:18][C:13]3([CH2:12][O:32][CH2:31]3)[C:14]2=[N:28]1
Reactant: Cc1ccc(S(=O)(=O)OCC2(CO)Oc3ccc([N+](=O)[O-])cc3-n3c2nn(C)c3=O)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1nc2n(c1=O)-c1cc([N+](=O)[O-])ccc1OC21COC1

Procedure:
(4-(Hydroxymethyl)-2-methyl-8-nitro-1-oxo-2,4-dihydro-1H-benzo[b][1,2,4]triazolo[4,3-d][1,4]oxazin-4-yl)methyl 4-methylbenzenesulfonate (1.1 g) was dissolved in anhydrous THF (100 mL). In an ice bath, 2.5 M n-butyl lithium in hexanes (1.05 mL, 1.1 eq.) was added to the reaction. The solution was reacted at 0° C. to room temperature, and then refluxed for three hours. The solvent was removed in vacuo. The residue was partitioned between EtOAc (100 mL) and 5% aqueous sodium bicarbonate (100 mL). The aqueous layer was extracted with EtOAc (2×100 mL). The organic layers were evaporated and purified by Combiflash chromatography (EtOAc in hexanes=20-100%) to give 2-methyl-8-nitrospiro[benzo[b][1,2,4]triazolo[4,3-d][1,4]oxazine-4,3′-oxetan]-1(2H)-one (150 mg, isomer a, m/z=290.92 (M+H)+) and 2-methyl-9-nitro-5H-spiro[benzo[b][1,2,4]triazolo[4,3-d][1,4]oxazepine-4,2′-oxiran]-1(2H)-one (250 mg, isomer b, m/z=290.92 (M+H)+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([O:21]C4C(F)=C(F)C(F)=C(F)C=4F)(=[O:20])=O)=[CH:15][CH:16]=3)[N:11]=[CH:10][N:9]=2)[C:5]([O:33][CH3:34])=[CH:4][C:3]=1[C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=1.[S:42]1[C:46]([NH2:47])=[N:45][CH:44]=[N:43]1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([NH:47][C:46]4[S:42][N:43]=[CH:44][N:45]=4)(=[O:20])=[O:21])=[CH:15][CH:16]=3)[N:11]=[CH:10][N:9]=2)[C:5]([O:33][CH3:34])=[CH:4][C:3]=1[C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=1
Reactant: COc1cc(-c2cccc(F)c2)c(Cl)cc1-c1ncnc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Reactant: Nc1ncns1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1cc(-c2cccc(F)c2)c(Cl)cc1-c1ncnc2cc(S(=O)(=O)Nc3ncns3)ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A vial was charged with perfluorophenyl 4-(2-chloro-3′-fluoro-5-methoxy-[1,1′-biphenyl]-4-yl)quinazoline-7-sulfonate (0.060 g, 0.098 mmol), 1,2,4-thiadiazol-5-amine (10.93 mg, 0.108 mmol), and cesium carbonate (0.096 g, 0.295 mmol). The vial was flushed with Ar (g), then acetonitrile (0.491 ml) was added. The reaction was stirred overnight at room temperature. The mixture was diluted with EtOAc and 1 N aq. HCl. The layers were separated, and the aq. layer was extracted with EtOAc (2×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (12-g Redi-Sep Gold column, 0-10% MeOH/DCM) to give 4-(2-chloro-3′-fluoro-5-methoxy-[1,1′-biphenyl]-4-yl)-N-(1,2,4-thiadiazol-5-yl)quinazoline-7-sulfonamide as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ=9.55-9.42 (m, 1H), 8.44-8.35 (m, 2H), 8.01 (td, J=2.0, 8.8 Hz, 1H), 7.96-7.89 (m, 1H), 7.67 (dd, J=1.5, 2.3 Hz, 1H), 7.63-7.54 (m, 1H), 7.49-7.41 (m, 2H), 7.38-7.28 (m, 2H), 3.75 (d, J=2.2 Hz, 3H). m/z (ESI) 529.8 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[C:7]([CH2:9][CH3:10])[CH:8]=1)#[N:2].Cl.[CH2:12]([OH:15])[CH2:13][CH3:14]>>[CH2:9]([C:7]1[CH:8]=[C:3]([C:1](=[NH:2])[O:15][CH2:12][CH2:13][CH3:14])[CH:4]=[N:5][CH:6]=1)[CH3:10]
Reactant: CCCO
Reactant: CCc1cncc(C#N)c1
Agent: Cl
Product: CCCOC(=N)c1cncc(CC)c1
Temperature: 25 °C
Reaction time: 30 h

Procedure:
After 3-cyano-5-ethylpyridine (2.07 g, 15.7 mmol) was dissolved in 1-propanol (80 ml) and hydrogen chloride gas was passed into the solution for 30 minutes, the reactor was tight sealed and the mixture was stirred at room temperature for 30 hours. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was neutralized with a saturated aqueous sodium carbonate solution and extracted with chloroform (100 ml×3). The chloroform layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product of propyl 5-ethyl-3-pyridinecarboximidate (2.94 g).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[N:17][N:18]([CH2:20][CH2:21][CH2:22][OH:23])[CH:19]=2)=[CH:11][C:3]=1[C:4]([N:6](CC)[CH2:7]C)=[O:5].NC1C(C(NC)=O)=C([Cl:35])C(Br)=CC=1>>[NH2:1][C:2]1[C:3]([C:4]([NH:6][CH3:7])=[O:5])=[C:11]([Cl:35])[C:12]([C:15]2[CH:16]=[N:17][N:18]([CH2:20][CH2:21][CH2:22][OH:23])[CH:19]=2)=[CH:13][CH:14]=1
Reactant: CNC(=O)c1c(N)ccc(Br)c1Cl
Reactant: CCN(CC)C(=O)c1cc(-c2cnn(CCCO)c2)ccc1N
Product: CNC(=O)c1c(N)ccc(-c2cnn(CCCO)c2)c1Cl
Yield: 33 %

Procedure:
Prepared analogously to Compound 3C replacing compound 3D with 6-amino-3-bromo-2-chloro-N-methylbenzamide (Compound 28D, 700 mg, 2.66 mmol) and to afford 274 mg of the title compound (33%). 1H NMR (400 MHz, CD3OD) δ=7.87 (s, 1H), 7.68 (s, 1H), 7.25 (d, J=8.6 Hz, 1H), 6.73 (d, J=8.6 Hz, 1H), 4.27 (t, J=7.0 Hz, 2H), 3.55 (t, J=6.2 Hz, 2H), 2.92 (s, 3H), 2.06 (quin, J=6.5 Hz, 2H). MS (ESI): m/z=309.10 [M+H]+. UPLC: tR=0.81 min (UPLC-TOF: polar—3 min).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]([N:18]([CH2:36][CH:37]([CH3:39])[CH3:38])[C@@H:19]1[CH2:24][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:22][C@H:21]([C:32]([O:34]C)=[O:33])[CH2:20]1)=[O:17].[OH-].[Na+]>CO>[C:28]([O:27][C:25]([N:23]1[CH2:24][C@@H:19]([N:18]([C:16]([C:8]2[N:7]([CH2:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=2)=[O:17])[CH2:36][CH:37]([CH3:38])[CH3:39])[CH2:20][C@@H:21]([C:32]([OH:34])=[O:33])[CH2:22]1)=[O:26])([CH3:30])([CH3:31])[CH3:29]
Reactant: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)OC)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)O)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Temperature: 50 °C
Reaction time: 1 h
Yield: 102.6 %

Procedure:
1-tert-Butyl 3-methyl(3R,5S)-5-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1,3-dicarboxylate (15 g) was dissolved in methanol (150 ml), 4N-aqueous sodium hydroxide solution (250 ml) was added, and the mixture was stirred at 50° C. for 1 hr. The solvent was evaporated under reduced pressure, and the residue was ice-cooled, neutralized with 2N hydrochloric acid, and extracted twice ethyl acetate (500 ml). The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was dried under reduced pressure to give the object product (15.0 g).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.C([O:12][C:13]([C:15]1[N:16]=[C:17]([N:24]2[CH2:29][CH2:28][CH:27]([O:30]C(=O)C(F)(F)F)[CH2:26][CH2:25]2)[N:18]([CH3:23])[C:19](=[O:22])[C:20]=1[OH:21])=O)C>CN(C)C=O>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:13]([C:15]2[N:16]=[C:17]([N:24]3[CH2:29][CH2:28][CH:27]([OH:30])[CH2:26][CH2:25]3)[N:18]([CH3:23])[C:19](=[O:22])[C:20]=2[OH:21])=[O:12])=[CH:4][CH:3]=1
Reactant: NCc1ccc(F)cc1
Reactant: CCOC(=O)c1nc(N2CCC(OC(=O)C(F)(F)F)CC2)n(C)c(=O)c1O
Solvent: CN(C)C=O
Product: Cn1c(N2CCC(O)CC2)nc(C(=O)NCc2ccc(F)cc2)c(O)c1=O
Yield: 48.1 %

Procedure:
A solution of 4-fluorobenzylamine (156 mg, 1.25 mmol) and 5-hydroxy-1-methyl-6-oxo-2-[4-(2,2,2-trifluoroacetoxy)piperidin-1-yl]-1,6-dihydropyrimidine-4-carboxylic acid ethyl ester (100 mg, 0.254 mmol) in dimethylformamide (3 mL) was heated at 120° C. for 2 h. Then, cooled and purified by preparative HPLC using MeOH/Water containg 0.1% TFA as an eluent. The fractions containing the product were combined and concentrated to afford title compound as a off-white solid (46 mg, 48%). 1H NMR (500 MHz, CDCl3) δ: 11.62 (s, 1H), 7.75 (br s, 1H), 7.31–7.28 (m, 2H), 7.04 (t, J=8.7 Hz, 2H), 4.56 (d, J=6.4 Hz, 2H), 3.95–3.89 (m, 1H), 3.52 (s, 3H), 3.28–3.23 (m, 2H), 2.88–2.83 (m, 2H), 2.02–1.96 (m, 2H), 1.73–1.66 (m, 2 H), 1.54 (br s, 1H). HRMS (M−H) calcd for C18H20FN4O4: 375.1469. found: 375.1472. Anal cald for C18H21FN4O4: C, 57.44; H, 5.62; N, 14.88. Found: C, 57.19; H, 5.55; N, 14.82.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[F:14][C:15]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([F:23])[C:16]=1Br.Cl>[Cu]Br.O1CCOCC1>[F:14][C:15]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([F:23])[C:16]=1[CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: COc1cc(F)c(Br)c(F)c1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Cu]Br
Agent: Cl
Agent: [H-]
Solvent: C1COCCO1
Product: CCOC(=O)C(C(=O)OCC)c1c(F)cc(OC)cc1F
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 74.1 %

Procedure:
Diethyl malonate (0.505 mol) is added to a mixture of sodium hydride (0.412 mol) and 1,4-dioxane (230 ml) at 40° C. within 3 hours. The mixture is stirred for 90 minutes at 60° C. and copper(I) bromide (0.402 mol) is added. A mixture of 2,6-difluoro-4-methoxybromobenzene (0.2 mol) and 1,4-dioxane (50 ml) is added. The reaction mixture is heated at 100° C. for 14 hours and cooled to 15° C. Hydrochloric acid (12N, 350 ml) is added slowly at 15 to 20° C. The organic phase is separated off and the aqueous phase is extracted with ethyl acetate (250 ml) and toluene (200 ml). The combined organic phases are concentrated in vacuo. The residue is filtered over silica gel, washed with petroleum ether/ethyl acetate (15:1) and the solvent is distilled off. The residue is distilled in vacuo to yield 44.8 g of the product as an oil, 128-136° C. at 0.018 mbar.