Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:21][C:22]([P:24](=[O:29])([O:27]C)[O:25][CH3:26])=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[Na+:30].[I-].CN(C=O)C.[K+].[Br-]>CC(C)=O.C1COCC1>[CH2:1]([O:21][C:22]([P:24](=[O:27])([O-:29])[O:25][CH3:26])=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[Na+:30]
Reactant: CCCCCCCCCCCCCCCCCCCCOC(=O)P(=O)(OC)OC
Agent: [Br-]
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCCCCCCCOC(=O)P(=O)([O-])OC

Procedure:
Demethylation of dimethyl 1-eicosanyloxycarbonylphosphonate with NaI was carried out as described in Example 8 above except for the solvent, which was a mixture of DMF (3 mL), THF (8 mL), and acetone (2 mL); yield 0.86 g (84%); mp 95-96° C.; IR (KBr): υ 2960, 2930, 2860, 1735, 1470, 1235, 1220 cm−1; 1H NMR (CDCl3+CD2OD) δ0.8-1.8 (m, 39H, CH3(CH2)18), 3.8 (d, 3H, P(ONa)(OCH3)), 4.2 (t, 2H, CH2O). Anal. Calcd. for C22H44O5NaP: C, 59.69; H, 10.04; N, 5.19; P, 7.00. Found: C, 59.94; H, 10.00; Na, 5.19; P, 7.06.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[C:5]2[C:17]1[N:22]=[C:21]([O:23][C@H:24]2[CH2:31][N:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29][CH2:28][C:25]32[CH2:27][CH2:26]3)[CH:20]=[N:19][CH:18]=1.CC1(C)CC(C)OB([C:47]([C:49]([F:52])([F:51])[F:50])=[CH2:48])O1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH:11]1[N:7]1[C:8]2[C:4](=[CH:3][C:2]([C:47]([C:49]([F:52])([F:51])[F:50])=[CH2:48])=[CH:10][CH:9]=2)[C:5]([C:17]2[N:22]=[C:21]([O:23][C@H:24]3[CH2:31][N:30]([C:32]([O:34][C:35]([CH3:37])([CH3:38])[CH3:36])=[O:33])[CH2:29][CH2:28][C:25]43[CH2:26][CH2:27]4)[CH:20]=[N:19][CH:18]=2)=[N:6]1
Reactant: C=C(B1OC(C)CC(C)(C)O1)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC2(CC2)[C@@H](Oc2cncc(-c3nn(C4CCCCO4)c4ccc(Br)cc34)n2)C1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: C=C(c1ccc2c(c1)c(-c1cncc(O[C@H]3CN(C(=O)OC(C)(C)C)CCC34CC4)n1)nn2C1CCCCO1)C(F)(F)F
Temperature: 95 °C
Reaction time: 1.5 h
Yield: 91.2 %

Procedure:
A brown solution of (4R)-tert-butyl 4-(6-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)-6-azaspiro[2.5]octane-6-carboxylate (469.5 mg, 0.803 mmol), 4,4,6-trimethyl-2-(3,3,3-trifluoroprop-1-en-2-yl)1,3,2-dioxaborinane (Frontier Scientific, Inc., Logan, Utah; 0.250 mL, 1.205 mmol), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (Xphos; Strem, Newburyport, Mass.; 38.3 mg, 0.080 mmol), Pd2(dba)3 (36.8 mg, 0.040 mmol), and potassium phosphate (853 mg, 4.02 mmol) in a mixture of dioxane (7.0 mL) and water (0.700 mL) was stirred under argon at 95° C. for 1.5 h. The reaction was cooled to RT, concentrated onto silica gel, and chromatographically purified (ISCO, 40 g silica gel column, 0-50% EtOAc/hexanes, 15 min, 254 nm) to provide (4R)-tert-butyl 4-(6-(1-(tetrahydro-2H-pyran-2-yl)-5-(3,3,3-trifluoroprop-1-en-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)-6-azaspiro[2.5]octane-6-carboxylate (438.7 mg, 0.732 mmol, 91% yield) as a white foam: MS (ESI, pos. ion) m/z: 600.3 (M+1).
Reaction SMILES: Br[C:2]1[CH:17]=[CH:16][C:5]2[C@:6]3([CH3:15])[C@@H:11]([CH2:12][CH2:13][C:4]=2[CH:3]=1)[NH:10][C:9](=[O:14])[CH2:8][CH2:7]3.[C:18]1(B(O)O)[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>ClCCl.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:26]1([C:2]2[CH:17]=[CH:16][C:5]3[C@:6]4([CH3:15])[C@@H:11]([CH2:12][CH2:13][C:4]=3[CH:3]=2)[NH:10][C:9](=[O:14])[CH2:8][CH2:7]4)[C:27]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:23]=[CH:24][CH:25]=1
Reactant: OB(O)c1cccc2ccccc12
Reactant: C[C@]12CCC(=O)N[C@@H]1CCc1cc(Br)ccc12
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: C[C@]12CCC(=O)N[C@@H]1CCc1cc(-c3cccc4ccccc34)ccc12
Yield: 69.8 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (500 mg, 1.70 mmol), tetrakis(triphenylphosphine) palladium (0) (80 mg, 0.07 mmol), 1-napthylboronic acid (439 mg, 2.55 mmol), 2.4 mL of 2M sodium carbonate and 4 mL of toluene, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 24 h. The mixture was cooled, diluted with dichloromethane (200 mL) and washed with brine (2×50 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (0-50% methanol/ethyl acetate eluent gradient) to give 405 mg (70%) of the title compound as a white solid. mp 247°-248°. FDMS: m/e=341. α[D]589 =+1.93 (c=1.04, methanol).
Reaction SMILES: Cl[C:2]1([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=2[OH:22])[C:7](=[O:8])[N:6]([CH3:9])[C:5]2[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=2[S:3]1.[CH3:23][OH:24]>>[OH:22][C:15]1[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:14]=1[C:2]1([O:24][CH3:23])[C:7](=[O:8])[N:6]([CH3:9])[C:5]2[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=2[S:3]1
Reactant: COc1ccc(O)c(C2(Cl)Sc3ccccc3N(C)C2=O)c1
Reactant: CO
Product: COc1ccc(O)c(C2(OC)Sc3ccccc3N(C)C2=O)c1
Yield: 85.3 %

Procedure:
A mixture of 2-chloro-3,4-dihydro-2-(2-hydroxy-5-methoxyphenyl)-4-methyl-3-oxo-2H-1,4-benzothiazine (14.0 g, compound No. 3) and methanol (200 ml) is stirred for 2 hours at room temperature, and the separated crystals are collected by filtration to give 11.8 g (85.3%) of the titled compound.
Reaction SMILES: [OH:1][CH:2]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH:11]=[C:10]([C:13]#[N:14])[C:9](=[O:15])[C:8]=2[CH:16]=1)[CH3:3].CC(C)=O.S(=O)(=O)(O)O>[O-2].[O-2].[O-2].[Cr+6].O>[C:2]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH:11]=[C:10]([C:13]#[N:14])[C:9](=[O:15])[C:8]=2[CH:16]=1)(=[O:1])[CH3:3]
Reactant: CC(O)c1ccc2occ(C#N)c(=O)c2c1
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [O-2]
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)c1ccc2occ(C#N)c(=O)c2c1

Procedure:
To a solution of 0.645 part of 6-(1-hydroxyethyl)-4-oxo-4H-1-benzopyran-3-carbonitrile in 20 parts by volume of acetone under stirring at room temperature is added dropwise over a period of 1 hour 1.0 part by volume of a solution which is prepared from chromium trioxide, 97% sulfuric acid and water in a ratio of 6.0 parts: 3.6 parts by volume: 18 parts by volume. The dark-green resins precipitated in the flask bottom is separated from the reaction mixture by decantation, and the solution is concentrated at room temperature to a one-third volume and then admixed with water to give precipitates. The precipitates collected by filtration is washed with water and recrystallized from ethyl acetate. The procedure yields 0.440 part of 6-acetyl-4-oxo-4H-1-benzopyran-3-carbonitrile as colorless crystals. Melting point: 170°-172° C
Reaction SMILES: [N:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N:3]([C:10]2[S:14][C:13]([C:15]([O:17]C)=O)=[C:12]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][C:28]([F:31])([F:30])[F:29])[CH:11]=2)[CH:2]=1.[NH3:32]>CO>[N:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N:3]([C:10]2[S:14][C:13]([C:15]([NH2:32])=[O:17])=[C:12]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][C:28]([F:30])([F:29])[F:31])[CH:11]=2)[CH:2]=1
Reactant: COC(=O)c1sc(-n2cnc3ccncc32)cc1OCc1ccccc1OC(F)(F)F
Reactant: N
Solvent: CO
Product: NC(=O)c1sc(-n2cnc3ccncc32)cc1OCc1ccccc1OC(F)(F)F

Procedure:
In a similar manner as described for example 28, 57 mg of methyl 5-(3H-imidazo[4,5-c]pyridin-3-yl)-3-{[2-(trifluoromethoxy)benzyl]oxy}thiophene-2-carboxylate and 6 ml of a saturated solution of ammonia in methanol yield the title compound.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]([NH:13][C:14]([C:16]3[C:17]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=4)=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:15])[CH:10]=[CH:11][CH:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].[C:38]([C:40]1[CH:41]=[C:42]([CH:45]=[CH:46][CH:47]=1)[CH2:43]Br)#[N:39]>CC(C)=O>[C:38]([C:40]1[CH:41]=[C:42]([CH:45]=[CH:46][CH:47]=1)[CH2:43][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:8]=[C:9]([NH:13][C:14]([C:16]3[C:17]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:31])[F:30])=[CH:24][CH:23]=4)=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:15])[CH:10]=[CH:11][CH:12]=2)[CH2:2][CH2:3]1)#[N:39]
Reactant: O=C(Nc1cccc(N2CCNCC2)c1)c1ccccc1-c1ccc(C(F)(F)F)cc1
Reactant: N#Cc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1cccc(CN2CCN(c3cccc(NC(=O)c4ccccc4-c4ccc(C(F)(F)F)cc4)c3)CC2)c1
Temperature: 25 °C
Yield: 26.8 %

Procedure:
To a solution of 4′-trifluoromethyl-biphenyl-2-carboxylic acid (3-piperazin-1-yl-phenyl)-amide (0.5 g) in acetone (20 mL) containing K2CO3 (0.19 g) was added 3-cyano-benzyl bromide (0.23 g) and the mixture was heated at reflux for 2 hours. The solution was cooled at room temperature and the salts were removed by filtration, washed with acetone and the filtrate was evaporated under reduced pressure. The residue was purified by crystallizatiori from AcOEt to give the title compound (0.17 g) as white crystals.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH2:12]([O:14][CH2:15][C:16]1[N:17]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:18]2[C:27]3[N:26]=[CH:25][CH:24]=[CH:23][C:22]=3[N:21]=[CH:20][C:19]=2[N:28]=1)[CH3:13].[Al]>C(Cl)(Cl)Cl>[CH2:12]([O:14][CH2:15][C:16]1[N:17]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:18]2[C:27]3[N:26]=[CH:25][CH:24]=[CH:23][C:22]=3[N+:21]([O-:9])=[CH:20][C:19]=2[N:28]=1)[CH3:13]
Reactant: CCOCc1nc2cnc3cccnc3c2n1Cc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Al]
Solvent: ClC(Cl)Cl
Product: CCOCc1nc2c[n+]([O-])c3cccnc3c2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Chloroperbenzoic acid (3.7 g, 13.4 mmol) was added in 3 portions to a solution of 2-ethoxymethyl-1-phenylmethyl-1H-imidazo[4,5-c][1,5]naphthyridine (3.9 g, 12.2 mmol) in chloroform (100 mL) in a flask covered with aluminum foil. The reaction mixture was stirred at ambient temperature overnight; and then it was washed twice with dilute aqueous sodium bicarbonate and once with brine. The chloroform layer was divided into two portions. One portion was used in the example below. The second portion was concentrated under vacuum. The residue was recrystallized from isopropyl alcohol to provide 2-ethoxymethyl-1-phenylmethyl-1H-imidazo[4,5-c][1,5]naphthyridine-5-oxide as a solid, m.p. 187.5-189° C. Analysis: Calculated for C19H18N4O2+¼ H2O: %C, 67.52; %H, 5.49; %N, 16.58; Found: %C, 67.56; %H, 5.36; %N, 16.77.
Reaction SMILES: [C:1]([O:5][C:6](=[O:41])[NH:7][C:8]1[C:13]([CH:14]([C:16]2[C:21]([N:22]([S:26]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([C:36]([F:39])([F:38])[F:37])[CH:30]=3)(=[O:28])=[O:27])[CH2:23][O:24][CH3:25])=[CH:20][C:19]([Cl:40])=[CH:18][N:17]=2)[OH:15])=[CH:12][CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2]>C1COCC1.O=[Mn]=O>[C:1]([O:5][C:6](=[O:41])[NH:7][C:8]1[C:13]([C:14]([C:16]2[C:21]([N:22]([S:26]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([C:36]([F:38])([F:37])[F:39])[CH:30]=3)(=[O:27])=[O:28])[CH2:23][O:24][CH3:25])=[CH:20][C:19]([Cl:40])=[CH:18][N:17]=2)=[O:15])=[CH:12][CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COCN(c1cc(Cl)cnc1C(O)c1cccnc1NC(=O)OC(C)(C)C)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: O=[Mn]=O
Solvent: C1CCOC1
Product: COCN(c1cc(Cl)cnc1C(=O)c1cccnc1NC(=O)OC(C)(C)C)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 60.8 %

Procedure:
A mixture of [3-({5-chloro-3-[(4-chloro-3-trifluoromethyl-benzene sulfonyl)-methoxymethyl-amino]-pyridin-2-yl}-hydroxy-methyl)-pyridin-2-yl]-carbamic acid tert-butyl ester (750 mg, 1.18 mmol) and MnO2 (512.6 mg, 5.9 mmol) in THF (10 mL) was stirred at 50° C. for overnight. The reaction mixture was cooled to room temperature, filtered through sintered funnel, washed with THF (2×10 mL), dried (anhydrous Na2SO4) and concentrated. The obtained residue was column purified (SiO2, 50% EtOAc-hexanes) to afford (3-{5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyrdine-2- carbonyl}-pyridin-2-yl)-carbamic acid tert-butyl ester (456 mg) 61% in yield. ESMS m/z (relative intensity): 635 (M+H)+ (100).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:11])=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=[O:6].[CH3:12]O>S(Cl)(Cl)=O.ClCCl>[CH3:12][O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][N:10]=[C:2]([Cl:1])[C:3]=1[F:11]
Reactant: CO
Reactant: O=C(O)c1ccnc(Cl)c1F
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccnc(Cl)c1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.2 %

Procedure:
2-Chloro-3-fluoroisonicotinic acid (3.30 g, 18.8 mmol) was suspended in thionyl chloride (40 ml) and heated under reflux for 2.5 h. The solvent was evaporated and the residue dried by means of azeotropic removal of water with toluene (100 ml) to afford a pale yellow oil. The oil was dissolved in dichloromethane (20 ml) and cooled to 0° C. before methanol (2.42 g, 75.3 mmol) was added dropwise to the solution over 15 min. On complete addition the mixture was allowed to warm to ambient temperature and stirred for 18 h. The solvent was evaporated and the mixture partitioned between water (75 ml) and dichloromethane (100 ml). The aqueous phase was extracted further with dichloromethane (100 ml), the organic layers were combined, washed with brine (75 ml), dried over anhydrous sodium sulphate, filtered and evaporated to give 2-chloro-3-fluoroisonicotinic acid methyl ester (3.32 g, 93%) as a pale yellow solid: δH (360 MHz, CDCl3) 3.99 (3H, s), 7.70 (1H, dd, J 5 and 5), 8.31 (1H, d, J 5).
Reaction SMILES: [CH:1]1([S:6]([C:9]2[N:14]=[CH:13][C:12]([CH:15]([O:19][CH:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[C:16](O)=[O:17])=[CH:11][CH:10]=2)(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:26][C:27]1[S:28][C:29]([O:32][C:33]2[CH:34]=[C:35]([CH:40]=[CH:41][CH:42]=2)[C:36]([O:38][CH3:39])=[O:37])=[CH:30][N:31]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CN1CCOCC1>C(Cl)Cl>[CH:1]1([S:6]([C:9]2[N:14]=[CH:13][C:12]([CH:15]([O:19][CH:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[C:16]([NH:26][C:27]3[S:28][C:29]([O:32][C:33]4[CH:34]=[C:35]([CH:40]=[CH:41][CH:42]=4)[C:36]([O:38][CH3:39])=[O:37])=[CH:30][N:31]=3)=[O:17])=[CH:11][CH:10]=2)(=[O:7])=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)c1cccc(Oc2cnc(N)s2)c1
Reactant: O=C(O)C(OC1CCOCC1)c1ccc(S(=O)(=O)C2CCCC2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)c1cccc(Oc2cnc(NC(=O)C(OC3CCOCC3)c3ccc(S(=O)(=O)C4CCCC4)nc3)s2)c1
Yield: 42.9 %

Procedure:
The compound of example A10 was obtained by similar method described in example A1 using 2-(6-cyclopentylsulfonyl-3-pyridyl)-2-tetrahydropyran-4-yloxy-acetic acid (Preparation 14; 0.200 g, 0.542 mmol), methyl 3-(2-aminothiazol-5-yl)oxybenzoate (Preparation 20, 0.162 g, 0.650 mmol), HOBt (0.087 g, 0.650 mmol), and EDCl (0.124 g, 0.650 mmol), N-methyl morpholine (0.136 g, 1.35 mmol) in DCM (8 mL) to provide the title compound (0.140 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([S:8][CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[N:5]=[C:4]2[CH2:14][CH2:15][CH2:16][C:3]=12.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:20][CH:19]=1>>[CH:9]1([S:8][C:6]2[N:5]=[C:4]3[CH2:14][CH2:15][CH2:16][C:3]3=[C:2]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:22][CH:23]=3)[CH:7]=2)[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: Clc1cc(SC2CCCC2)nc2c1CCC2
Reactant: CCOC(=O)Cc1ccc(N)cc1
Product: CCOC(=O)Cc1ccc(Nc2cc(SC3CCCC3)nc3c2CCC3)cc1
Yield: 108.8 %

Procedure:
Following general procedure B1, 4-chloro-2-(cyclopentylthio)-6,7-dihydro-5H-cyclopenta[b]pyridine (0.130 g, 0.51 mmol) was reacted with ethyl 2-(4-aminophenyl)acetate (0.137 g, 0.77 mmol) to afford crude product (0.220 g) as a colorless gum. MW=396.55. 1H NMR (CDCl3, 300 MHz) δ 7.27 (d, J=8.5 Hz, 2H), 7.12 (d, J=8.5 Hz, 2H), 6.74 (s, 1H), 5.62 (s, 1H), 4.17 (q, J=7.0 Hz, 2H), 3.93-3.79 (m, 1H), 3.60 (s, 2H), 3.52-3.46 (m, 2H), 2.97 (t, J=7.5 Hz, 2H), 2.74 (t, J=7.5 Hz, 2H), 2.22-2.02 (m, 4H), 1.83-1.51 (m, 6H), 1.27 (t, J=7.0 Hz, 3H); APCI MS m/z 397 [M+H]+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH:7]=[O:8])[CH2:3][CH2:2]1.[C:9](#[N:12])[CH:10]=[CH2:11].[OH-].C([N+](C)(C)C)C1C=CC=CC=1.Cl>O1CCOCC1>[CH:7]([C:4]1([CH2:11][CH2:10][C:9]#[N:12])[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)=[O:8]
Reactant: C=CC#N
Reactant: O=CC1CCOCC1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: Cl
Agent: [OH-]
Solvent: C1COCCO1
Product: N#CCCC1(C=O)CCOCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 53 %

Procedure:
A solution of tetrahydro-2H-pyran-4-carbaldehyde (1.0 g, 8.77 mmol) and acrylonitrile (0.6 mL, 8.77 mmol) in dioxane (5 mL) was cooled to 0° C., treated with benzyltrimethylammonium hydroxide (0.04 mL, 40% in methanol), stirred at 0° C. for 30 minutes, warmed to room temperature, and stirred for 18 hours. The mixture was neutralized with 1N HCl and extracted with ethyl acetate. The organic phase was washed with aqueous saturated NaHCO3, dried (Na2SO4), filtered, and concentrated. The oil was purified by flash chromatography eluting with 0% to 50% ethyl acetate/hexane to provide the desired product as a colorless oil (0.777 g, 53% yield).
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)(=[O:4])=[O:3].[NH:15]1C2C(=CC=CC=2)C[C:16]1=O>CN.O1CCCC1>[CH3:16][NH:15][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)(=[O:4])=[O:3]
Reactant: O=C1Cc2cc(S(=O)(=O)Cl)ccc2N1
Reactant: O=C1Cc2ccccc2N1
Agent: CN
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Yield: 88 %

Procedure:
A suspension of 3.38 g of 5-chlorosulfonyl-2-oxindole from the oxindole O-17 in 10 mL of 2 M methylamine in tetrahydrofuran was stirred at room temperature for 4 hours at which time a white solid was present. The precipitate was collected by vacuum filtration, washed twice with 5 mL of water each time and dried under vacuum at 40° C. overnight to give 3.0 g (88% yield) of 5-methylaminosulfonyl-2-oxindole.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:11][CH3:12])=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.[H-].[Na+].[CH3:15]I>CN(C)C=O.O.C(OCC)(=O)C>[Br:1][C:2]1[C:3]([O:11][CH3:12])=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:15])[N:6]=[CH:5]2
Reactant: COc1c(Br)ccc2[nH]ncc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1c(Br)ccc2c1cnn2C
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 65.6 %

Procedure:
A solution of 5-bromo-4-methoxy-1H-indazole (0.125 g, 0.550 mmol) in N,N-dimethylformamide (2.20 mL) was treated with sodium hydride (0.0166 g, 0.659 mmol) at 20° C. and then stirred at 20° C. for 30 min. The resultant reaction mixture was treated with methyl iodide (0.0410 mL, 0.658 mmol) and stirred at 20° C. for 1 h. The reaction mixture was diluted with water and ethyl acetate. Layers were separated and the organic layer was washed with brine, dried with sodium sulfate, filtered, and concentrated in vacuo to give the crude product. Purification by flash column chromatography (100% hexanes to 100% EtOAc) gave the desired product (87 mg, 66%) as a white solid. LCMS calculated for C9H10BrN2O (M+H)+: m/z=241.0, 243.0. found: 240.9, 242.9.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:14]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])=[C:13]([F:23])[C:8]2=[N:9][O:10][C:11]([CH3:12])=[C:7]2[CH:6]=1)=[O:4].C1COCC1.[Li+].[OH-].Cl>O>[Cl:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[NH:15][C:14]1[C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]2[C:8]([C:13]=1[F:23])=[N:9][O:10][C:11]=2[CH3:12]
Reactant: COC(=O)c1cc2c(C)onc2c(F)c1Nc1ccccc1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1onc2c(F)c(Nc3ccccc3Cl)c(C(=O)O)cc12
Reaction time: 1 h
Yield: 90.7 %

Procedure:
To a solution of 6-(2-chlorophenylamino)-7-fluoro-3-methyl-benzo[c]-isoxazole-5-carboxylic acid methyl ester (55) (100 mg, 0.299 mmol) in 6:1 THF:water (3.5 mL) was added LiOH (0.60 ml of a 1 M solution in water). After 1 hour, the reaction was acidified to pH 1 with 1 N HCl, diluted with water and extracted with EtOAc. The combined organic extracts were washed with water, dried (MgSO4) and concentrated to give the desired product (56) (87 mg, 91%). MS APCI (−) m/z 319, 321 (M+, Cl pattern) detected. 1H NMR (400 MHz, CH3OD) δ 8.45 (s, 1H), 7.38 (dd, 1H), 7.20 (m, 1H), 6.91 (m, 2H), 2.88 (s, 3H): 19F NMR (376 MHz, CH3OD) −136.40 (s).
Reaction SMILES: CS(O[CH2:6][C:7]([NH:10][C:11]1[CH:16]=[C:15]([Cl:17])[N:14]=[C:13](Cl)[N:12]=1)([CH3:9])[CH3:8])(=O)=O.C(=O)([O-])[O-:20].[K+].[K+]>O1CCOCC1.O>[Cl:17][C:15]1[CH:16]=[C:11]2[NH:10][C:7]([CH3:9])([CH3:8])[CH2:6][N:12]2[C:13](=[O:20])[N:14]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(COS(C)(=O)=O)Nc1cc(Cl)nc(Cl)n1
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC1(C)Cn2c(cc(Cl)nc2=O)N1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of 2-((2,6-dichloropyrimidin-4-yl)amino)-2-methylpropyl methanesulfonate (3.00 g, 9.55 mmol) in 1,4-dioxane (15 mL) and water (15 mL) was added potassium carbonate (4.62 g, 33.4 mmol). The reaction mixture was stirred at 80° C. for 2 h, filtered, extracted with ethyl acetate (5 mL×2), dried over anhydrous Na2SO4, filtered and concentrated to give the crude product, which was used into next step without further purification.
Reaction SMILES: [C:1]([C:4]1[CH:28]=[CH:27][C:7]([C:8]([NH:10][C:11]([N:13]2[CH2:18][CH2:17][CH:16]([CH2:19][O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:15][CH2:14]2)=[O:12])=[O:9])=[CH:6][CH:5]=1)(=S)[NH2:2].IC.CC(C)=O.C([O-])(=O)C.[NH4+:39]>ClCCl.C(O)C>[C:1]([C:4]1[CH:28]=[CH:27][C:7]([C:8]([NH:10][C:11]([N:13]2[CH2:18][CH2:17][CH:16]([CH2:19][O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:15][CH2:14]2)=[O:12])=[O:9])=[CH:6][CH:5]=1)(=[NH:39])[NH2:2]
Reactant: [NH4+]
Reactant: CCOC(=O)COCC1CCN(C(=O)NC(=O)c2ccc(C(N)=S)cc2)CC1
Agent: CC(=O)[O-]
Solvent: CI
Solvent: ClCCl
Solvent: CC(C)=O
Product: CCOC(=O)COCC1CCN(C(=O)NC(=O)c2ccc(C(=N)N)cc2)CC1
Yield: 57.7 %

Procedure:
In a similar manner to Example 1, the product from step (d) (380 mg), iodomethane (2 ml) and acetone (40 ml) were reacted at ambient temperature and the product so obtained was reacted with ammonium acetate (800 mg), ethanol (40 ml) and dichloromethane (20 ml). This yielded an oily residue which was purified by column chromatography on silica eluting with 10% ethanol/dichloromethane to give ethyl N-[N-(4-amidinobenzoyl)carbamoyl]piperidin-4-ylmethoxyacetate (210 mg) which was used without further purification.