Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH2:10][CH3:11])[C:6]=1[C:7](Cl)=[O:8].[C:12]1([S:18]([N:21]2[C:29]3[CH:28]=[C:27]([Sn:30]([CH3:33])([CH3:32])[CH3:31])[CH:26]=[C:25]([NH2:34])[C:24]=3[CH:23]=[N:22]2)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH2:10][CH3:11])[C:6]=1[C:7]([NH:34][C:25]1[CH:26]=[C:27]([Sn:30]([CH3:33])([CH3:32])[CH3:31])[CH:28]=[C:29]2[C:24]=1[CH:23]=[N:22][N:21]2[S:18]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:20])=[O:19])=[O:8]
Reactant: C[Sn](C)(C)c1cc(N)c2cnn(S(=O)(=O)c3ccccc3)c2c1
Reactant: CCn1ncc(Cl)c1C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCn1ncc(Cl)c1C(=O)Nc1cc([Sn](C)(C)C)cc2c1cnn2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
4-Chloro-1-ethyl-1H-pyrazole-5-carbonyl chloride (122 mg) in DCM (5 ml) was added over 5 min to 1-(phenylsulfonyl)-6-(trimethylstannanyl)-1H-indazol-4-amine (250 mg) in DCM (10 ml) and pyridine (0.05 ml). The reaction was stirred at room temperature for 1.5 h. Saturated sodium bicarbonate (aq) (20 ml) was added and the reaction stirred vigorously before the DCM was passed through a hydrophobic frit and evaporated to dryness. The residue was passed through a silica cartridge, preconditioned with cyclohexane. The silica cartridge was washed with cyclohexane:diethyl ether (1:1, v/v), then diethyl ether. The product containing ether fraction was evaporated to dryness to give title compound, 303 mg.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[CH2:12]1[O:14][CH2:13]1>CN(C=O)C>[OH:14][CH2:13][CH2:12][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: C1CO1
Reactant: c1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: OCCn1ccc2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
11.7 g of indole in 500 ml of DMF were treated with 4 g of sodium hydride dispersed in mineral oil. After 1 hour the mixture was cooled in an ice bath and 10 ml of ethylene oxide were added. The mixture was allowed to warm to room temperature and was then stirred for 2 hours. The solvent was evaporated and the residue was treated with 50 ml of water and neutralized with 2M hydrochloric acid. The product was extracted into dichloromethane, the solvent was evaporated and the residue was chromatographed with ethyl acetate/petroleum ether to give 7.6 g of 1-(2-hydroxyethyl)indole.
Reaction SMILES: [Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([CH3:13])[C:3]=1[CH2:14]O.S(Cl)([Cl:18])=O>>[Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([CH3:13])[C:3]=1[CH2:14][Cl:18]
Reactant: O=S(Cl)Cl
Reactant: Cc1nn(-c2ccccc2)c(Cl)c1CO
Product: Cc1nn(-c2ccccc2)c(Cl)c1CCl

Procedure:
6.1 g of 5-chloro-4-hydroxymethyl-3-methyl-1-phenylpyrazole are added portionwise to 50 ml of thionylchloride. The mixture is refluxed for 2 hours, the excess thionylchloride distilled off, the oily product treated with water and then extracted with ether. The dried ethereal extract is evaporated in vacuo yielding 6.1 g of oily 5-chloro-4-chloromethyl-3-methyl-1-phenylpyrazole which, without further purification, is used in the next reaction step.
Reaction SMILES: O[CH:2]=[CH:3][C:4]([C:6]1([CH3:12])[CH2:9][CH:8]([CH2:10][CH3:11])[CH2:7]1)=[O:5].S(Cl)([Cl:15])=O>C1C=CC=CC=1>[Cl:15]/[CH:2]=[CH:3]/[C:4]([C:6]1([CH3:12])[CH2:9][CH:8]([CH2:10][CH3:11])[CH2:7]1)=[O:5]
Reactant: O=S(Cl)Cl
Reactant: CCC1CC(C)(C(=O)C=CO)C1
Solvent: c1ccccc1
Product: CCC1CC(C)(C(=O)/C=C/Cl)C1
Reaction time: 15 h

Procedure:
A solution of 5.8 g of 1-hydroxy-3-(3-ethyl-1-methylcyclobutyl)-prop-1-en-3-one (prepared in Example 4A) in 100 ml of benzene was stirred under an argon atmosphere and 7 ml of thionyl chloride in 10 ml of benzene was added dropwise. The resulting solution was stirred for about 15 hr. Excess solvent was removed by distillation at atmospheric pressure and the residue was then distilled in vacuo to yield 4.2 g of the title compound having the following physical characteristics:
Reaction SMILES: [C:1]1([CH3:29])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]([C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:13][CH:12]([NH2:27])[C:11]2=[O:28])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[C:30]1([CH3:39])[CH:35]=[CH:34][CH:33]=[C:32]([N:36]=[C:37]=[O:38])[CH:31]=1>O1CCCC1>[C:1]1([CH3:29])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]([C:21](=[O:26])[C:22]([CH3:24])([CH3:25])[CH3:23])[CH2:13][CH:12]([NH:27][C:37]([NH:36][C:32]3[CH:33]=[CH:34][CH:35]=[C:30]([CH3:39])[CH:31]=3)=[O:38])[C:11]2=[O:28])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1cccc(N=C=O)c1
Reactant: Cc1ccccc1C(=O)CN1C(=O)C(N)CN(C(=O)C(C)(C)C)c2ccccc21
Solvent: C1CCOC1
Product: Cc1cccc(NC(=O)NC2CN(C(=O)C(C)(C)C)c3ccccc3N(CC(=O)c3ccccc3C)C2=O)c1
Yield: 54.5 %

Procedure:
1-(2-Toluoylmethyl)-2-oxo-3-amino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (411 mg) was dissolved in tetrahydrofuran. m-Tolyl isocyanate (146 mg) was added thereto, and the resultant mixture was stirred at room temperature for 30 minutes. The solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1), to thereby obtain 300 mg of the title compound.
Reaction SMILES: C([O:3][C:4](=[O:36])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:25]=[C:26]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH:27]=[CH:28][CH:29]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])C.[OH-].[Na+].Cl.C(OCC)(=O)C>C(O)C>[C:26]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:27]=[CH:28][CH:29]=[C:24]([C:20]2[O:21][C:22]([CH3:23])=[C:18]([CH2:17][CH2:16][O:15][C:12]3[CH:13]=[CH:14][C:9]([O:8][C:5]([CH3:7])([CH3:6])[C:4]([OH:36])=[O:3])=[CH:10][CH:11]=3)[N:19]=2)[CH:25]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3cccc(-c4ccccc4)c3)oc2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1oc(-c2cccc(-c3ccccc3)c2)nc1CCOc1ccc(OC(C)(C)C(=O)O)cc1
Temperature: 25 °C

Procedure:
A stirred solution of 2-{4-[2-(2-biphenyl-3-yl-5-methyloxazol-4-yl)ethoxy]-phenoxy}-2-methyl propionic acid ethyl ester (345.2 mg, 0.711 mmol) in ethanol (8.9 mL) was treated with NaOH(aq) (0.854 mL of a 5M solution), and heated at reflux for 1 h. The hot solution was acidified to pH 1 with 1M HCl (6 mL). The mixture was cooled to ambient temperature, then further cooled to 0° C. before filtering the product. Following washing with H2O, the product was dried under vacuum at 50° C. to yield 226.2 mg (70%) as a white, crystalline solid: Rf=0.2 in 6:4 ethyl acetate:hexanes; 1H NMR (400 MHz, CDCl3) δ8.21 (s, 1H), 7.95 (d, J=7.2 Hz, 1H), 7.64-7.62 (m, 3H), 7.48 (t, J=7.8 Hz, 1H), 7.43 (t, J=7.8 Hz, 2H), 7.35 (t, J=7.2 Hz, 1H), 6.88-6.77 (m, 4H), 4.18 (t, J=6.4 Hz, 2H), 2.99 (t, J=6.4 Hz, 2H), 2.44 (s, 3H), 1.51 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([CH3:17])[C:10](=[N:13][N+:14]([O-:16])=[O:15])SC)=[CH:4][CH:3]=1.[CH3:18][NH2:19]>C(#N)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([CH3:17])[C:10]([NH:19][CH3:18])=[N:13][N+:14]([O-:16])=[O:15])=[CH:4][CH:3]=1
Reactant: CSC(=N[N+](=O)[O-])N(C)Cc1ccc(Cl)nc1
Reactant: CN
Solvent: CC#N
Product: CNC(=N[N+](=O)[O-])N(C)Cc1ccc(Cl)nc1
Temperature: 70 °C
Reaction time: 2 h
Yield: 72.8 %

Procedure:
A mixture of 0.82g of 1-(6-chloro-3-pyridylmethyl)-1,2-dimethyl-3-nitroisothiourea, 0.464g of 40% methylamine aqueous solution and 10ml of acetonitrile was stirred for 2 hours at 70° C., and concentrated. The residue was purified by a column chromatography [developing solution: dichloromethane-methanol [10:1]) to afford 0.56g of 1-(6-chloro-3-pyridylmethyl)-1,3-dimethyl-2-nitroguanidine (Compound No. 8).
Reaction SMILES: [O:1]=[O+][O-].[CH2:4]([C:7]1[CH:16]=[C:15]2[C:10]([C:11]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:12][C:13]([C:17]#[N:18])=[N:14]2)=[CH:9][CH:8]=1)[CH:5]=C.CSC>C(OCC)(=O)C>[O:1]=[CH:5][CH2:4][C:7]1[CH:16]=[C:15]2[C:10]([C:11]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:12][C:13]([C:17]#[N:18])=[N:14]2)=[CH:9][CH:8]=1
Reactant: O=[O+][O-]
Reactant: C=CCc1ccc2c(-c3ccccc3)cc(C#N)nc2c1
Solvent: CCOC(C)=O
Solvent: CSC
Product: N#Cc1cc(-c2ccccc2)c2ccc(CC=O)cc2n1
Reaction time: 1 h

Procedure:
Ozone was bubbled into a solution of 7-allyl-4-phenylquinoline-2-carbonitrile (1.5 g, 5.6 mmol) in ethyl acetate (100 mL) at −78° C. for 1.5 h. Nitrogen was then bubbled into the solution and methylsulfide (2.1 mL, 28 mmol) was added. The reaction was brought back to room temperature, stirred for 1 h and concentrated to give the title compound. MS (+ESI): 273 (M+H)+.
Reaction SMILES: [Si]([O:8][CH2:9][C@:10]1([CH3:35])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:29]5[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)(C(C)(C)C)(C)C.Cl>CO.O1CCOCC1>[CH3:35][C@@:10]1([CH2:9][OH:8])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:29]5[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1
Reactant: CC(C)(C)[Si](C)(C)OC[C@@]1(C)Cc2nnc(C3(c4ccc(-c5cccnc5)cc4)CC3)n2CCS1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: C[C@]1(CO)Cc2nnc(C3(c4ccc(-c5cccnc5)cc4)CC3)n2CCS1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.3 %

Procedure:
The compound (455 mg, 0.93 mmol) obtained in Example 4-3) was dissolved in methanol (4 mL). A 4 M solution (2.24 mL) of hydrochloric acid in dioxane was added to the solution, and the mixture was stirred at room temperature for 1 h. The solvent was distilled off, the residue was dissolved in a mixed solvent of methylene chloride (60 mL) and methanol (3 mL), and the mixture was separated into organic and aqueous layers by the addition of saturated aqueous sodium hydrogencarbonate (20 mL). The organic layer was washed with saturated sodium chloride solution and then dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (elution solvent: methanol/ethyl acetate=0% to 50%) to obtain the title compound (231 mg, 66%) in a white solid form.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[NH:16][C:15](=[O:17])[CH2:14][CH2:13][CH2:12]1.Br[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[N:16]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]([F:28])([F:29])[F:30])=[CH:22][CH:21]=2)[C:15](=[O:17])[CH2:14][CH2:13][CH2:12]1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Reactant: COc1cccc(OC)c1C1CCCC(=O)N1
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1ccc(OC(F)(F)F)cc1

Procedure:
Prepared according to the described general procedure 4 (GP4) by reaction of 6-(2,6-dimethoxyphenyl)piperidin-2-one with commercially available 1-(bromomethyl)-4-(trifluoromethoxy)benzene. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions E): tR=0.82 min.; [M+H]+: 410.08 g/mol.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1>CN(C=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:22][C:21]2[CH:24]=[CH:25][C:18]([F:17])=[CH:19][CH:20]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: Fc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCc2ccc(F)cc2)cc1
Temperature: 100 °C
Reaction time: 48 h
Yield: 95.9 %

Procedure:
A mixture of 4-nitrophenol (1.39 g, 10 mmol), potassium carbonate (1.38 g, 10 mmol) and 4-fluorobenzyl bromide (1.89 g, 10 mmol) in 20 ml of anhydrous DMF was stirred at 100° C. for 2 days. After cooling to room temperature, the reaction mixture was poured into 200 ml of ice-water with stirring. The solid was filtered and washed with water and dried to give 2.37 g (96%) of 1-nitro-4-(4-fluorobenzyloxy)-benzene as yellow solids.
Reaction SMILES: FC(F)(F)C([O:5][C:6](=[O:11])[C:7]([F:10])([F:9])[F:8])=O.[F:14][CH2:15][C:16]([NH:18]O)=[O:17]>>[F:14][CH2:15][C:16]([NH:18][O:5][C:6](=[O:11])[C:7]([F:8])([F:9])[F:10])=[O:17]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: O=C(CF)NO
Product: O=C(CF)NOC(=O)C(F)(F)F
Yield: 93 %

Procedure:
Trifluoroacetic anhydride, 71 ml (0.5 mol), was added dropwise to a 37.22 g (0.4 mol) sample of powdered 2-fluoroacetohydroxamic acid. The reaction mixture became liquid and warmed spontaneously to 60°. After cooling, the reaction mixture was evaporated to dryness under reduced pressure to give 70.3 g (93%) of N--(fluoroacetyl)--O--(trifluoroacetyl)hydroxylamine as a colorless, crystalline residue: mp 56°-59°; 1H NMR (CDCl3) δ5.05 ppm (d, J=47 Hz, 2H) and 9.8 ppm (NH); 19F NMR (CDCl3) δ-233.8 ppm (t, J=47 Hz, 1F) and 73.8 ppm (s, 3F).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]([N+:15]([O-])=O)=[C:12]([NH2:14])[CH:13]=2)[CH2:4][CH2:3]1>[Pd].C(OCC)(=O)C>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:13]=[C:12]([NH2:14])[C:11]([NH2:15])=[CH:10][CH:9]=2)[CH2:6][CH2:7]1
Reactant: CN1CCN(c2ccc([N+](=O)[O-])c(N)c2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CN1CCN(c2ccc(N)c(N)c2)CC1
Reaction time: 17 h
Yield: 116.6 %

Procedure:
A suspension of 5-(4-Methyl-piperazin-1-yl)-2-nitro-phenylamine (513.0 mg, 2.17 mmol) [See Kim, Jung Sun; et al.; J. Med. Chem.; 39; 992 (1996) for the synthesis of this compound] and 10% palladium on carbon (200.8 mg) in ethyl acetate (50 mL) was shaken under 40 psi H2 for 17 hours. The catalyst was removed by filtration through a Celite pad, and the mixture concentrated to afford crude 4-(4-Methyl-piperazin-1-yl)-benzene-1,2-diamine (522 mg) as a yellow foam. This crude diamine was added to a solution of aldehyde 19f (853.7 mg, 2.17 mmol) and elemental sulfur (83 mg, 2.60 mmol) in anhydrous dimethylformamide (40 mL), and the solution heated in an 80° C. oilbath for 6 hours. After cooling to room temperature, the solution was diluted with ethyl acetate (150 mL) and washed with water (50 mL) and saturated aqueous sodium chloride solution (50 mL). The organic layer was dried over magnesium sulfate, filtered, concentrated, and purified by silica gel chromatography (1:20:400 concentrated aqueous NH4OH: EtOH:CH2Cl2), affording 20a (623 mg, 50%) as an orange-brown foam: Rf=0.20 (10% ethanol in dichloromethane); 1H NMR (DMSO-d6) [Some peaks are doubled due to tautomeric isomerization] δ2.23 (s, 3H), 2.49 (m, 4H), 3.10 (m, 4H), 3.71 (s, 3H), 5.80 (s, 2H), 6.91 (m, 4H), 7.36 and 7.47 (2 d, 3H together, J=8.3, 8.7 Hz), 7.64 (d, 1H, J=8.9 Hz), 7.77 (m, 3H), 7.99 (m, 1H), 8.25 (d, 1H, J=7.2 Hz), 8.53 (s, 1H), 8.62 (2 s, 1H together), 9.39 (s, 1H), 12.78 and 12.83 (2 s, 1H together). Anal. (C36H33N7O.0.9 H2O) C, H, N.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:27][CH2:26][CH2:25][C@H:8]3[S:9](=[O:24])(=[O:23])[C:10]([CH3:22])([CH3:21])[C:11]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[N:12][C@:7]3([CH3:28])[C:6]=2[CH:29]=1.[Cl:30][C:31]1[CH:32]=[C:33]([CH:40]=[CH2:41])[C:34]([C:37](O)=[O:38])=[N:35][CH:36]=1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Cl:30][C:31]1[CH:32]=[C:33]([CH:40]=[CH2:41])[C:34]([C:37]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[O:27][CH2:26][CH2:25][C@H:8]4[S:9](=[O:23])(=[O:24])[C:10]([CH3:22])([CH3:21])[C:11]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[N:12][C@:7]4([CH3:28])[C:6]=3[CH:29]=2)=[O:38])=[N:35][CH:36]=1
Reactant: C=Cc1cc(Cl)cnc1C(=O)O
Reactant: CC(C)(C)OC(=O)NC1=N[C@]2(C)c3cc(N)ccc3OCC[C@H]2S(=O)(=O)C1(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=Cc1cc(Cl)cnc1C(=O)Nc1ccc2c(c1)[C@@]1(C)N=C(NC(=O)OC(C)(C)C)C(C)(C)S(=O)(=O)[C@@H]1CCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of tert-butyl ((4aR,11bR)-10-amino-3,3,11b-trimethyl-4,4-dioxido-4a,5,6,11b-tetrahydro-3H-benzo[6,7]oxepino[4,5-b][1,4]thiazin-2-yl)carbamate (0.080 g, 0.19 mmol) in DCM (2.0 ml) were added 5-chloro-3-vinylpicolinic acid (0.036 g, 0.20 mmol), triethylamine (0.053 ml, 0.38 mmol) and HATU (0.079 g, 0.21 mmol). The mixture was stirred at room temperature for 2 h. The reaction mixture was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g), eluting with a gradient of 10% to 60% EtOAc in hexane, to provide tert-butyl ((4aR,11bR)-10-(5-chloro-3-vinylpicolinamido)-3,3,11b-trimethyl-4,4-dioxido-4a,5,6,11b-tetrahydro-3H-benzo[6,7]oxepino[4,5-b][1,4]thiazin-2-yl)carbamate (0.11 g, 0.19 mmol, 99% yield) as a white solid. m/z (ESI) 589.0 (M+H)+.
Reaction SMILES: C(C1C2[C:7](=CN=CC=2)[N:6](CC(O)=O)[CH:5]=1)(=O)C.[NH2:17][C@@H:18]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=1[F:29])[CH2:19][CH2:20]O>>[Cl:28][C:24]1[C:23]([F:29])=[C:22]([C@H:18]([NH2:17])[CH2:19][CH2:20][N:6]([CH3:7])[CH3:5])[CH:27]=[CH:26][CH:25]=1
Reactant: CC(=O)c1cn(CC(=O)O)c2cnccc12
Reactant: N[C@H](CCO)c1cccc(Cl)c1F
Product: CN(C)CC[C@@H](N)c1cccc(Cl)c1F

Procedure:
was prepared using similar procedures as described for the synthesis of (3-acetyl-pyrrolo[2,3-c]pyridin-1-yl)-acetic acid in Scheme C4 from (R)-3-amino-3-(3-chloro-2-fluoro-phenyl)-propan-1-ol. 1H-NMR (400 MHz, DMSO): δ (ppm): 8.89 (m, 2H), 7.73 (m, 2H), 7.39 (t, 1H), 4.69 (m, 1H), 3.13 (m, 1H), 2.98 (m, 1H), 2.73 (s, 6H), 2.47 (m, 1H), 2.34 (1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=O)[C:5]2([CH2:13][CH2:14][O:15][CH3:16])[CH3:12].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH2:6][C:5]2([CH2:13][CH2:14][O:15][CH3:16])[CH3:12]
Reactant: COCCC1(C)C(=O)Nc2ccc(F)cc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COCCC1(C)CNc2ccc(F)cc21
Temperature: 70 °C
Reaction time: 1 h

Procedure:
Under an argon atmosphere 0.12 g (0.54 mmol) 5-fluoro-3-(2-methoxy-ethyl)-3-methyl-1,3-dihydro-indol-2-one were placed in 20 mL THF. 0.56 mL (0.56 mmol) of a 1M lithium aluminium hydride solution in 10 mL THF were added dropwise. The reaction mixture was stirred for 1 h at 70° C., then mixed with water and dried, filtered and concentrated to dryness by rotary evaporation.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][C:6]([OH:8])=O)[CH2:3][CH2:2]1.C(N(C(C)C)C(C)C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH2:45]([O:47][C:48]([C:50]1([CH2:56][CH2:57][O:58][CH3:59])[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1)=[O:49])[CH3:46]>>[CH2:45]([O:47][C:48]([C:50]1([CH2:56][CH2:57][O:58][CH3:59])[CH2:51][CH2:52][N:53]([C:6](=[O:8])[CH2:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[CH2:54][CH2:55]1)=[O:49])[CH3:46]
Reactant: O=C(O)CCC1CC1
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(CCOC)CCN(C(=O)CCC2CC2)CC1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 36.4 %

Procedure:
To a solution of 3-cyclopropyl-propionic acid (0.342 g) in acetronitril (15 ml) were added under an argon atmosphere N-ethyldiisopropylamine (0.775 g, 1.03 ml) and BOP (1.328 g and the mixture was stirred for 50 minutes at RT. Then 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (0.646 g) were added and the mixture was stirred for 12 h at RT. The reaction mixture was partitioned between ethyl acetate and aqueous 1M HCl, the layers were separated and the aqueous layer washed with 2M aqueous KHCO3 then dried over Na2SO4. The solvent was evaporated off, the residue purified by flash chromatography (methylene chloride/AcOEt, gradient from 0 to 30%) to give 1-(3-cyclopropyl-propionyl)-4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester, (0.34 g) as a yellow oil that was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[CH:16][N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[CH2:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1B(O)O)[CH3:25]>>[CH2:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[CH:16][N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1)[CH3:25]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Reactant: CCc1ccccc1B(O)O
Product: CCc1ccccc1-c1ccc2c(c1)OCCn1cc(-c3ncnn3C(C)C)nc1-2

Procedure:
Following the procedures of Example 475, 8-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene 194 was reacted with 2-ethylphenylboronic acid to give 477. MS (ESI+) 400.2. 1H NMR (400 MHz, DMSO) δ 8.47 (d, J=8.2 Hz, 1H), 7.95 (s, 1H), 7.92 (s, 1H), 7.38-7.31 (m, 2H), 7.30-7.23 (m, 1H), 7.20 (d, J=7.3 Hz, 1H), 7.12 (dd, J=8.2, 1.7 Hz, 1H), 6.97 (d, J=1.6 Hz, 1H), 5.93 (hept, J=6.2 Hz, 1H), 4.65-4.41 (m, 4H), 2.61 (q, J=7.6 Hz, 2H), 1.50 (d, J=6.6 Hz, 6H), 1.07 (t, J=7.5 Hz, 3H)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C@:8]23[CH2:16][N:15]([C:17]4[N:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=4)[CH2:14][C@H:13]2[CH2:12][S:11][C:10]([NH:24][C:25](=[O:32])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:9]3)[CH:5]=[CH:6][CH:7]=1.[F:33][C:34]1[C:35]([C:41](O)=[O:42])=[N:36][CH:37]=[C:38]([F:40])[CH:39]=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C>ClCCl>[C:25]([NH:24][C:10]1[S:11][CH2:12][C@@H:13]2[CH2:14][N:15]([C:17]3[N:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=3)[CH2:16][C@:8]2([C:4]2[CH:3]=[C:2]([NH:1][C:41]([C:35]3[C:34]([F:33])=[CH:39][C:38]([F:40])=[CH:37][N:36]=3)=[O:42])[CH:7]=[CH:6][CH:5]=2)[N:9]=1)(=[O:32])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=C(O)c1ncc(F)cc1F
Reactant: Nc1cccc([C@]23CN(c4ncc(F)cn4)C[C@H]2CSC(NC(=O)c2ccccc2)=N3)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NC1=N[C@@]2(c3cccc(NC(=O)c4ncc(F)cc4F)c3)CN(c3ncc(F)cn3)C[C@H]2CS1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.5 %

Procedure:
N-[(4aR,7aS)-7a-(3-Aminophenyl)-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-2-yl]benzamide (0.30 g, 0.67 mmol) is dissolved in dichloromethane (10 mL) and 3,5-difluoropyridine-2-carboxylic acid (138 mg, 0.87 mmol), 1-hydroxybenzotriazole (185 mg, 1.34 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (169 mg, 0.87 mmol) are added. Diisopropylethylamine (0.35 mL, 2 mmol) is added and the reaction is stirred at room temperature overnight. The reaction is purified directly with silica gel chromatography eluting with a 0-100% ethyl acetate/hexanes gradient to give the title compound (330 mg, 84%). ES/MS (m/e): 590 (M+H).
Reaction SMILES: [NH2:1][C@H:2]([C:6]([NH:8][CH:9]([CH:18]([OH:31])[CH2:19][O:20][C:21]1[C:26]([F:27])=[C:25]([F:28])[CH:24]=[C:23]([F:29])[C:22]=1[F:30])[CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:7])[CH:3]([CH3:5])[CH3:4].[C:32]([O:36][C:37]([CH2:39][N:40]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH:42]=[C:41]1[C:49](O)=[O:50])=[O:38])([CH3:35])([CH3:34])[CH3:33].CN1CCOCC1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[C:32]([O:36][C:37]([CH2:39][N:40]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH:42]=[C:41]1[C:49]([NH:1][C@H:2]([C:6]([NH:8][CH:9]([CH:18]([OH:31])[CH2:19][O:20][C:21]1[C:22]([F:30])=[C:23]([F:29])[CH:24]=[C:25]([F:28])[C:26]=1[F:27])[CH2:10][C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])=[O:7])[CH:3]([CH3:5])[CH3:4])=[O:50])=[O:38])([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)[C@H](N)C(=O)NC(CC(=O)OC(C)(C)C)C(O)COc1c(F)c(F)cc(F)c1F
Reactant: CC(C)(C)OC(=O)Cn1c(C(=O)O)cc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)c1cc2ccccc2n1CC(=O)OC(C)(C)C)C(=O)NC(CC(=O)OC(C)(C)C)C(O)COc1c(F)c(F)cc(F)c1F
Yield: 65.8 %

Procedure:
The procedure of Example 77 was followed using the product of Example 106 (400.0 mg, 0.90 mmol), 1-[(tert-butyloxycarbonyl)methyl]indole-2-carboxylic acid (200 mg, 0.73 mmol), NMM (0.1 ml), HOBt (246 mg, 1.63 mmol), and EDAC (304 mg, 1.60 mmol) in methylene chloride to prepare the titled product (341 mg, 68%).