Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([CH:8]=O)[CH:4]=[N:3]1.[H-].[Na+].C(OP([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])(OCC)=O)C.CN(C)C=O>O>[CH3:1][N:2]1[C:6]([CH3:7])=[C:5](/[CH:8]=[CH:20]/[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:4]=[N:3]1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: Cc1c(C=O)cnn1C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1cnn(C)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.6 %

Procedure:
A mixture of 1,5-dimethyl-1H-pyrazole-4-carbaldehyde (400 mg), sodium hydride (60% in oil, 155 mg), ethyl diethylphosphonoacetate (795 mg) and N,N-dimethylformamide (5 ml) was stirred at room temperature for 1 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated. Recrystallization of the residue from ethyl acetate-hexane gave ethyl (2E)-3-(1,5-dimethyl-1H-pyrazol-4-yl)acrylate (304 mg, 49%) as colorless prism crystals. melting point: 82-83° C.
Reaction SMILES: [F:1][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[CH:15]=[CH:14][C:13]([NH2:16])=[N:12]2)=[CH:7][CH:6]=1)([F:4])[CH3:3].[C:17]1([C:23]2[O:27][CH:26]=[N:25][C:24]=2[C:28](O)=[O:29])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[F:4][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[CH:15]=[CH:14][C:13]([NH:16][C:28]([C:24]3[N:25]=[CH:26][O:27][C:23]=3[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[O:29])=[N:12]2)=[CH:7][CH:6]=1)([F:1])[CH3:3]
Reactant: O=C(O)c1ncoc1-c1ccccc1
Reactant: CC(F)(F)c1ccc(Cn2ccc(N)n2)o1
Product: CC(F)(F)c1ccc(Cn2ccc(NC(=O)c3ncoc3-c3ccccc3)n2)o1

Procedure:
Following general procedure B, starting from 1-[5-(1,1-difluoro-ethyl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and 5-phenyl-oxazole-4-carboxylic acid.
Reaction SMILES: [H-].[Na+].[SH:3][C:4]1[N:9]2[CH:10]=[CH:11][N:12]=[C:8]2[CH:7]=[CH:6][CH:5]=1.[CH2:13]([C:20]1[C:21](=[O:38])[N:22]([CH2:33][CH2:34][CH2:35][CH2:36]Cl)[C:23](=[O:32])[N:24]2[CH2:29][CH2:28][CH2:27][S:26](=[O:31])(=[O:30])[C:25]=12)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[I-].[Na+]>CN(C)C=O.O>[N:12]1[CH:11]=[CH:10][N:9]2[C:4]([S:3][CH2:36][CH2:35][CH2:34][CH2:33][N:22]3[C:21](=[O:38])[C:20]([CH2:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)=[C:25]4[S:26](=[O:31])(=[O:30])[CH2:27][CH2:28][CH2:29][N:24]4[C:23]3=[O:32])=[CH:5][CH:6]=[CH:7][C:8]=12
Reactant: Sc1cccc2nccn12
Reactant: O=c1c(Cc2ccccc2)c2n(c(=O)n1CCCCCl)CCCS2(=O)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c(Cc2ccccc2)c2n(c(=O)n1CCCCSc1cccc3nccn13)CCCS2(=O)=O
Reaction time: 0.5 h

Procedure:
To a suspension of 0.22 g (5.5 mmol) of 60% oily sodium hydride in 30 ml of N,N-dimethylformamide, 0.83 g (5.5 mmol) of 5-mercaptoimidazo[1,2-a]pyridine was added at room temperature, followed by stirring for 30 minutes. To this mixture, 1.98 g (5 mmol) of 9-benzyl-7-(4-chlorobutyl)-1,1-dioxo-3,4-dihydro-2H,6H-pyrimido[6,1-b][1,3]thiazine-6,8(7H)-dione and 0.82 g (5.5 mmol) of sodium iodide were added, followed by stirring at 100° C. for 2 hours. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate 3 times. The organic layer was washed with water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, ethyl acetate→ethyl acetate/ethanol=10/1) to yield 1.95 g (78.2%, white powder) of the desired product.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][NH:21][CH2:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].Cl[C:31]([O:33][CH2:34][CH3:35])=[O:32]>>[CH2:1]([NH:3][C:4](=[O:5])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][N:21]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)Cl
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CNCC3)cc1
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CN(C(=O)OCC)CC3)cc1

Procedure:
Method as example 34 using (S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)phenyl)urea (example 12) and ethyl chloroformate as starting materials.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([O:7][C:8]2[C:9]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:10][C:11]([C:18]([OH:20])=[O:19])=[CH:12][C:13]=2[S:14]([NH2:17])(=[O:16])=[O:15])=[CH:5][CH:6]=1.Cl[CH2:27][C:28]#[N:29]>CN(C=O)C>[NH2:17][S:14]([C:13]1[CH:12]=[C:11]([CH:10]=[C:9]([N:21]2[CH2:22][CH2:23][CH2:24][CH2:25]2)[C:8]=1[O:7][C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1)[C:18]([O:20][CH2:27][C:28]#[N:29])=[O:19])(=[O:16])=[O:15]
Reactant: N#CCCl
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc(N2CCCC2)c1Oc1ccccc1
Solvent: CN(C)C=O
Product: N#CCOC(=O)c1cc(N2CCCC2)c(Oc2ccccc2)c(S(N)(=O)=O)c1

Procedure:
In a similar manner to Example 2, piretanide can be reacted with chloroacetonitrile in DMF to yield cyanomethyl 3-aminosulfonyl-4-phenoxy-5-(1-pyrrolidinyl)benzoate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[C:7]([OH:13])=[C:6]([Cl:14])[CH:5]=1>CO.O.[Fe]>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:5]=[C:6]([Cl:14])[C:7]([OH:13])=[C:8]([NH2:10])[CH:9]=1
Reactant: COC(=O)c1cc(Cl)c(O)c([N+](=O)[O-])c1
Agent: [Fe]
Solvent: O
Solvent: CO
Product: COC(=O)c1cc(N)c(O)c(Cl)c1
Yield: 67.3 %

Procedure:
A solution of 3-chloro-4-hydroxy-5-nitro-benzoic acid methyl ester (500 mg, 2.16 mmol) in methanol (22 mL) was added within 10 min to a mixture of iron powder (410 mg, 7.34 mmol) ammonium chloride (647 mg, 12.1 mmol) in water (22 mL). The reaction mixture was heated at reflux over 16 h, then after cooling filtered through a pad of diatomaceous earth. The filtrate was extracted with ethyl acetate, dried (MgSO4), and evaporated. Chromatography (SiO2, ethyl acetate/heptane 7:3) afforded 3-amino-5-chloro-4-hydroxy-benzoic acid methyl ester (293 mg, 68%). Light yellow solid, MS (ISP)=200.1 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:21])[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.[Br-:22]>[Al+3].[Cl-].[Cl-].[Cl-]>[Br:22][CH:10]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1)[C:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:21]
Reactant: [Br-]
Reactant: COc1ccc(C(=O)CCc2ccc([N+](=O)[O-])cc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Product: COc1ccc(C(=O)C(Br)Cc2ccc([N+](=O)[O-])cc2)cc1
Yield: 96.1 %

Procedure:
A procedure similar to step 3 of Example 1 was used, 1-(4-methoxy-phenyl)-3-(4-nitro-phenyl)-propan-1-one prepared in the step 3 and bromide were used as starting materials, and anhydrous AlCl3 was used as catalyst, the obtained product was white crystal in a yield of 96.1%, mp: 120-122 └. 1H-NMR (CDCl3, 400 MHz) δ: 3.46 (1H, dd, J=14.28, 7.28 Hz), 3.74 (1H, dd, J=14.28, 7.28 Hz), 3.88 (3H, s, OCH3), 5.27 (1H, t, J=7.28 Hz, CHBr), 6.94 (2H, d, J=8.96 Hz, ArH), 7.46 (2H, d, J=8.60 Hz, ArH), 7.96 (2H, d, J=8.96 Hz, ArH), 8.16 (2H, d, J=8.60 Hz, ArH); ESI-MS: 366.1 (M+2, 93), 364.2 (M, 100).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])(=[O:3])[CH3:2].C([N-]C(C)C)(C)C.[Li+].[CH2:25]([Si:27]([CH2:37][CH3:38])([CH2:35][CH3:36])[C:28]1[O:32][CH:31]=[C:30]([CH:33]=[O:34])[CH:29]=1)[CH3:26]>O1CCCC1>[OH:34][CH:33]([C:30]1[CH:29]=[C:28]([Si:27]([CH2:35][CH3:36])([CH2:37][CH3:38])[CH2:25][CH3:26])[O:32][CH:31]=1)[CH2:2][C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:3]
Reactant: CCCCCCCCCCCCOC(C)=O
Reactant: CC[Si](CC)(CC)c1cc(C=O)co1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCOC(=O)CC(O)c1coc([Si](CC)(CC)CC)c1

Procedure:
A solution of dodecyl acetate (240 mg, 1.04 mmol) in tetrahydrofuran (2 ml) was added to a solution of lithium diisopropylamide (1.04 mmol; =generated from 0.15 ml of diisopropylamine and 0.42 ml n-butyl lithium at -78°) in tetrahydrofuran (10 ml) at -78° under argon. After 1h, a solution of 5-triethylsilyl-3-furaldehyde (200 mg, 0.95 mmol) in tetrahydrofuran (1 ml) was added. Stirring was continued for 15h while the cooling bath attained room temperature. The mixture was quenched with water and was extracted thoroughly with ethyl acetate. Evaporation of the dried (magnesium sulfate) extracts gave an oil which was purified by a silica column using 20% ethyl ether/hexane to give the titled ester.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9]([S:10][CH2:11][CH3:12])=[C:8]([C:13]([NH2:15])=[O:14])[CH:7]=[N:6][N:5]2[CH:16]=1.[C:17]([C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1)#[N:18].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[C:17]([C:19]1[CH:24]=[CH:23][C:22]([C:2]2[CH:3]=[C:4]3[C:9]([S:10][CH2:11][CH3:12])=[C:8]([C:13]([NH2:15])=[O:14])[CH:7]=[N:6][N:5]3[CH:16]=2)=[CH:21][CH:20]=1)#[N:18]
Reactant: CCSc1c(C(N)=O)cnn2cc(Br)cc12
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: CCSc1c(C(N)=O)cnn2cc(-c3ccc(C#N)cc3)cc12
Temperature: 125 °C

Procedure:
A mixture of 6-bromo-4-(ethylthio)pyrrolo[1,2-b]pyridazine-3-carboxamide (1.2 g, 4.00 mmol), 4-cyanophenylboronic acid (0.881 g, 6.00 mmol), palladium (II) acetate (0.090 g, 0.400 mmol) and 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbyphenyl (XPhos) (0.381 g, 0.800 mmol) was pumped under vacuum and backfilled with nitrogen three times. Next, potassium phosphate, tribasic, 2M (7.60 mL, 15.19 mmol) and dioxane (Volume: 30 mL) were quickly added. The resulting orange suspension was again pumped under vacuum and backfilled with nitrogen three times. The reaction vessel was sealed and heated behind a blast shield in a 125° C. oil bath for 4 h. LCMS and HPLC showed that the desired product was formed, but the reaction was incomplete. The mixture was cooled to room temperature and 4-cyanophenylboronic acid (0.366 g, 3.00 mmol), palladium (II) acetate (0.045 g, 0.200 mmol) and 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (0.191 g, 0.400 mmol) were added. The resulting mixture was again pumped under vacuum and backfilled with nitrogen three times. The reaction vessel was sealed and heated behind a blast shield in a 125° C. oil bath for 1.5 h. The reaction mixture was partitioned between EtOAc (250 ml) and water (250 ml). The two phases were separated. The aqueous phase was extracted with EtOAc (2×50 mL). The combined organic phase was washed with brine (100 mL), dried (MgSO4) and concentrated to give a yellow solid. The solid residue was treated with Et2O (50 mL), stirred for 30 min, filtered, and washed with 1:1 mixture of Et2O-hexanes (2×15 mL) to give a yellow solid (889 mg). 1H NMR, HPLC and LCMS showed that the main component was the desired product, but the material was impure. The filtrate was found to contain a minor amount of the desired product. The impure material was treated with Et2O (50 mL), stirred for 30 min, filtered, washed with 1:1 mixture of Et2O-hexanes (2×15 mL) to give the title compound as yellow solid (787 mg). 1H NMR showed some improvement, but the material was still impure. The mixture was taken to the next reaction without purification.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[O:6][C:7]1[C:16]2[C:11](=[C:12]([NH2:17])[CH:13]=[CH:14][CH:15]=2)[N:10]=[CH:9][CH:8]=1.[Cl:23][C:24]1[CH:32]=[CH:31][C:30]([CH2:33][NH:34][C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37])=[CH:29][C:25]=1[C:26](O)=[O:27].C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:23][C:24]1[CH:32]=[CH:31][C:30]([CH2:33][NH:34][C:35](=[O:40])[C:36]([CH3:38])([CH3:37])[CH3:39])=[CH:29][C:25]=1[C:26]([NH:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2[O:6][C:5]1[CH:18]=[CH:19][CH:20]=[C:3]([C:2]([F:1])([F:21])[F:22])[CH:4]=1)=[O:27]
Reactant: Nc1cccc2c(Oc3cccc(C(F)(F)F)c3)ccnc12
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)Nc2cccc3c(Oc4cccc(C(F)(F)F)c4)ccnc23)c1
Yield: 20.4 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using 4-(3-(trifluoromethyl)phenoxy)quinolin-8-amine (Intermediate-11, 40 mg, 0.132 mmol), 2-chloro-5-(pivalamidomethyl)benzoic acid (Intermediate-5, 200 mg, 0.743 mmol), oxalyl chloride (140 mg, 1.11 mmol), DMF (1 drop) and DIPEA (52 mg, 0.40 mmol) in CH2Cl2 (5 mL) to afford 15 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.5 (s, 1H), 9.01 (d, J=7.8 Hz, 1H), 8.60 (d, J=4.8 Hz, 1H), 8.05 (d, J=8.7 Hz, 1H), 7.71-7.60 (m, 4H), 7.48-7.38 (m, 4H), 6.64 (d, J=5.1 Hz, 1H), 6.05 (br s, 1H), 4.49 (d, J=6.0 Hz, 2H), 1.23 (s, 9H); MS [M+H]+: 556.19.
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19])=[O:10].[NH2:20][CH2:21][C:22]1[NH:23][C:24](=[O:32])[C:25]2[CH:31]=[CH:30][CH:29]=[N:28][C:26]=2[N:27]=1>CN(C1C=CN=CC=1)C.ClCCl>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH2:12][O:11][C:9](=[O:10])[NH:20][CH2:21][C:22]1[NH:23][C:24](=[O:32])[C:25]2[CH:31]=[CH:30][CH:29]=[N:28][C:26]=2[N:27]=1
Reactant: NCc1nc2ncccc2c(=O)[nH]1
Reactant: O=C(Cl)OCc1ccccc1Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCc1nc2ncccc2c(=O)[nH]1)OCc1ccccc1Cl
Reaction time: 8 h

Procedure:
Triethylamine (0.26 ml), 2-chlorobenzyl chloroformate ([39545-31-8], 130 mg) and DMAP (8 mg) were added to a solution of 2-aminomethyl-3H-pyrido[2,3-d]pyrimidin-4-one (25.1, 150 mg) in dichloromethane (3 ml). The mixture was kept overnight at r.t., and then diluted with dichloromethane and washed with water. After drying (Na2SO4) and evaporation of the solvent, the title compound was isolated from the reaction mixture by preparative, reversed-phase HPLC (Agilent Zorbax XdB C18 column, solvent gradient 5-95% CH3CN in 0.1% TFA(aq) over 7 min, flow rate 30 ml/min). MS: m/e=343.0 [M−H−].
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][OH:9].[H][H]>[Ru]>[NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][CH2:8][OH:9]
Reactant: [H][H]
Reactant: OCCc1ccccn1
Agent: [Ru]
Product: OCCC1CCCCN1

Procedure:
Hydrogenations were carried out by charging solvent, 246 g of 2-pyridineethanol, and varying amounts of 5% ruthenium on carbon (5% Ru/C) into a pressure vessel capable of agitation, agitating the resulting mixture and pressurizing the vessel and its contents to 500 psi with hydrogen. Under constant hydrogen pressure and continued agitation, the reaction mixture was heated to 150° C. until hydrogen uptake ceased. The pressure vessel and its contents were cooled, vented and the catalyst removed with vacuum filtration. Upon distillation of the filtrate, 2-piperidineethanol was obtained and analyzed on two separate gc columns (6′ CW 20M 160° C. and 15M DB-1 80° C.→220° C.@ 16° C./m capillary column) to provide product yield and composition of the distillate. The results are provided in Table III.
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[BH4-].[Na+].[Cl-].[Ce+3].[Cl-].[Cl-].Cl>CO.O>[CH:1]1([OH:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C1C=Cc2ccccc21
Agent: Cl
Agent: [BH4-]
Agent: [Ce+3]
Solvent: CO
Solvent: O
Product: OC1C=Cc2ccccc21
Reaction time: 0.17 h
Yield: 96.5 %

Procedure:
The indenone from Example 109 (0.5 g) is reduced with NaBH4 (0.05 g) and cerium chloride (0.5 g) in methanol (20 ml). The reaction is ended after 10 minutes and the reaction mixture is poured into water. The pH is taken to 5 by means of dilute HCl and the mixture is extracted with ethyl acetate. It is washed with water and the solvent is evaporated. Indenol (0.49 g; m.p. 134° C.) is obtained (yield: 99%; compound no. 110).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Li]CCCC.[C:19]([S:23]([N:25]=[CH:26][CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[O:24])([CH3:22])([CH3:21])[CH3:20].[NH4+].[Cl-]>C1COCC1.O.CCOCC>[C:3]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH:26]([NH:25][S:23]([C:19]([CH3:22])([CH3:21])[CH3:20])=[O:24])[CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30]
Reactant: COC(=O)CCC=NS(=O)C(C)(C)C
Reactant: Ic1ccccc1-c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: COC(=O)CCC(NS(=O)C(C)(C)C)c1ccccc1-c1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A cooled (−78° C.) solution of commercially available 2-iodo-1,1′-biphenyl (1.916 g; 6.84 mmol) in anh. THF (62 ml), under nitrogen, was treated dropwise with a solution of 1.6 M n-BuLi in hexanes (4.27 ml; 6.84 mmol). The resulting solution was further stirred at −78° C. for 10 min. A solution of methyl 4-((tert-butylsulfinyl)imino)butanoate (1.500 g; 6.84 mmol) in anh. THF (8 ml) was added to the cooled reaction mixture, and stirring was continued from −78° C. to 0° C. over 1 h. The resulting reaction mixture was treated successively with aq. sat. NH4Cl (80 ml), Et2O (250 ml) and water (75 ml). The separated organic layer was then washed with brine (75 ml), dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (DCM/MeOH=25/1) afforded methyl 4-([1,1′-biphenyl]-2-yl)-4-(1,1-dimethylethylsulfinamido)butanoate. LC-MS (conditions A): tR=0.85 min.; [M+H]+: 374.12 g/mol.
Reaction SMILES: [Br:1][C:2]1[C:6]2[C:7]([NH2:12])=[N:8][CH:9]=[C:10](I)[C:5]=2[S:4][CH:3]=1.C([Sn](CCCC)(CCCC)/[CH:18]=[CH:19]/[CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])CCC.[F-].[K+]>C1(C)C=CC=CC=1.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>[NH2:12][C:7]1[C:6]2[C:2]([Br:1])=[CH:3][S:4][C:5]=2[C:10](/[CH:18]=[CH:19]/[CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:9][N:8]=1
Reactant: CCCC[Sn](/C=C/CNC(=O)OC(C)(C)C)(CCCC)CCCC
Reactant: Nc1ncc(I)c2scc(Br)c12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NC/C=C/c1cnc(N)c2c(Br)csc12
Temperature: 110 °C

Procedure:
A mixture of Example 21A (1.0 g, 2.8 mmol), tert-butyl (2E)-3-(tributylstannyl)-2-propenylcarbamate (prepared according to the procedure described in Synthesis, 1991, (12), 1201, 1.5 g, 3.36 mmol), and potassium flouride (195 mg, 3.36 mmol) in toluene (10 mL) was degassed, treated with Pd(PPh3)4 (194 mg, 0.17 mmol), degassed, and heated to 110° C. for 14 hours under a nitrogen atmosphere. The mixture was concentrated and purified by flash chromatography on silica gel with dichloromethane/ethyl acetate (6:4) to provide the desired product (1.3 g, 3.36 mmol). 1H NMR (DMSO-d6, 400 MHz) δ 7.93 (s, 1H), 7.35 (s, 1H), 6.55 (d, 1H), 6.21 (dt, 1H), 5.81 (br s, 2H), 4.73 (br s, 1H), 3.98 (s, 2H), 1.48 (s, 9H); reverse phase HPLC (5% to 95% acetonitrile over 25 minutes, 1 mL/min, 254 nm, hypersil HS 100 Å, C18, 5 μm, 250×4.6 column) Rt=15.5 minutes; MS m/e 385.1.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13]C)=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][O:28][CH2:27][C:26]2=[O:31])=[CH:17][CH:16]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:13])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][O:28][CH2:27][C:26]2=[O:31])=[CH:17][CH:16]=1
Reactant: COC(=O)c1c[nH]c2cc(Cl)c(-c3ccc(OCCCN4CCOCC4=O)cc3)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1c[nH]c2cc(Cl)c(-c3ccc(OCCCN4CCOCC4=O)cc3)cc12
Temperature: 70 °C
Reaction time: 24 h
Yield: 5.3 %

Procedure:
To a solution of methyl 6-chloro-5-{4-[3-(3-oxomorpholin-4-yl)propoxy]phenyl}-1H-indole-3-carboxylate (55 mg, 0.22 mmol) in methanol (8 mL) was added 1.0M aq. NaOH (2.0 mL, 2.0 mmol). The mixture was stirred at 70° C. for 24 hours. The mixture was adjusted to pH 7 and purified by reverse phase HPLC to give the title compound as a white solid (5 mg, 9% yield). MS (ES+) 429.1 (M+H)+. 1H NMR (400 MHz, CD3OD): δ 7.90 (m, 2H), 7.5 (s, 1H), 7.29 (d, 2H), 6.92 (d, 2H), 4.05 (m, 4H), 3.83 (t, 2H), 3.58 (t, 2H), 3.42 (t, 2H), 2.05 (m, 2H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[CH:18]=[N:19][C:20]([N:23](C(OC(C)(C)C)=O)[CH3:24])=[CH:21][CH:22]=2)=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:24][NH:23][C:20]1[CH:21]=[CH:22][C:17]([C:15]([NH:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[O:16])=[CH:18][N:19]=1
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNc1ccc(C(=O)NC2CCNCC2)cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The above prepared 4-{[6-(tert-butoxycarbonyl-methyl-amino)-pyridine-3-carbonyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester (0.495 g, 1.14 mmol) was dissolved in 14 ml of CH2Cl2 and treated with 2.8 ml of trifluoroacetic acid. After stirring for 3 h at ambient temperature, TLC indicated the absence of starting material. Evaporation of all volatiles left 0.704 g of the title compound as trifluoroacetate as light brown amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N+:3]=1[O-:9].S(=O)(=O)(O)O.[N+:15]([O-])([O-:17])=[O:16].[K+].[OH-].[NH4+]>>[Cl:1][C:2]1[CH:7]=[C:6]([N+:15]([O-:17])=[O:16])[C:5]([F:8])=[CH:4][N+:3]=1[O-:9]
Reactant: [O-][n+]1cc(F)ccc1Cl
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [NH4+]
Product: O=[N+]([O-])c1cc(Cl)[n+]([O-])cc1F
Temperature: 120 °C
Yield: 59.2 %

Procedure:
2-Chloro-5-fluoropyridine-N-oxide (10, 3.5 g, 23.7 mmol) was gradually added to 46 mL of concentrated sulfuric acid, followed by 10 g of potassium nitrate with stirring. The reaction mixture was heated at 120° C. for 2 h, cooled and poured onto 160 g of crushed ice. The solution was neutralized by dropwise addition of 28% ammonium hydroxide with stirring, while the temperature was maintained below 15° C. with an ice bath. The light yellow crystals which precipitated were collected by filtration, washed with ice water, and dried to yield 2.7 g (59%) of product. A small sample was purified by silica gel column chromatography (CH2Cl2/EtOAc, 4:1, v/v, Rf 0.71): mp 131-132° C.; 1H NMR (DMSO-d6) δ8.70 (m, 1 H, 3-H), 9.12 (m, 1 H, 6-H). Analysis calculated for C5H2ClFN2O3: C, 31.19; H, 1.05; N, 14.55. Found: C, 31.36; H, 1.16; N, 14.75.