Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Cl-].[CH3:4][O:5][C:6]1[CH:31]=[CH:30][C:9]([CH2:10][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:8][C:7]=1[CH3:32].[O:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH:34]1[O:39][CH2:40][C:41]1[N:42]=[C:43]([C:48]2[CH:53]=[CH:52][C:51]([C:54]([F:57])([F:56])[F:55])=[CH:50][CH:49]=2)[S:44][C:45]=1[CH:46]=O>C(Cl)Cl.C(Cl)(Cl)(Cl)Cl>[CH3:4][O:5][C:6]1[CH:31]=[CH:30][C:9](/[CH:10]=[CH:46]/[C:45]2[S:44][C:43]([C:48]3[CH:53]=[CH:52][C:51]([C:54]([F:56])([F:57])[F:55])=[CH:50][CH:49]=3)=[N:42][C:41]=2[CH2:40][O:39][CH:34]2[CH2:35][CH2:36][CH2:37][CH2:38][O:33]2)=[CH:8][C:7]=1[CH3:32]
Reactant: COc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1C
Reactant: O=Cc1sc(-c2ccc(C(F)(F)F)cc2)nc1COC1CCCCO1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(/C=C/c2sc(-c3ccc(C(F)(F)F)cc3)nc2COC2CCCCO2)cc1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100 %

Procedure:
To a suspension of NaH (60% dispersion in mineral oil, 242mg, 6.32mmoles, 1.4eq) in dry CH2Cl2(15ml) was added (4-Methoxy-3-methylbenzyl)(triphenyl)phosphonium chloride (2.62g, 6.32mmoles, 1.4eq). This was allowed to stir at room temperature for 1.5hours followed by the dropwise addition of 4-[(tetrahydro-2H-pyran-2-yloxy)methyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole-5-carbaldehyde (1.68g, 4.51mmoles, 1eq) in anhydrous carbon tetrachloride (25ml). The resulting reaction mixture was refluxed overnight at which point (after cooling to room temperature) the reaction washed with 1N NaOH, H2O, brine, dried over Na2SO4and concentrated in vacuo to yield a >100% yield of a light green oil. The crude material was used without purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:9]=1)[C:7]#[N:8].[Cl:10]N1C(=O)CCC1=O>C(#N)C>[Cl:10][C:3]1[C:2]([OH:1])=[CH:9][C:6]([C:7]#[N:8])=[CH:5][N:4]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: N#Cc1cncc(O)c1
Solvent: CC#N
Product: N#Cc1cnc(Cl)c(O)c1
Temperature: 107 °C
Yield: 21.4 %

Procedure:
A mixture of 5-hydroxy-nicotinonitrile (2.0 g, 16.66 mmol), and N-chlorosuccinimide (3.3 g, 25.0 mmol) in acetonitrile (33 mL) was heated in a sealed tube at 107° C. overnight. Acetonitrile was removed under reduced pressure, the residue was diluted with EtOAc (100 mL). The organic layer was washed with water (10 mL) and brine (2×10 mL), dried over Na2SO4, filtered, and concentrated to give brown oil. Purification was accomplished by flash chromatography on silica gel using 20-80% EtOAc/hexanes gradient elution to yield the title compound (0.55 g, 36%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.70 (s, 1H), 8.35 (d, J=2.0 Hz, 1H), 7.67 (d, J=2.0 Hz, 1H); MS (ES) m/z: 153 (M−1)−.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8]([OH:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16]Cl>>[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16][O:1][C:2]1[C:3]([C:8]([O:10][CH2:16][C:15]2[CH:18]=[CH:19][CH:20]=[C:13]([O:12][CH3:11])[CH:14]=2)=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cccc(CCl)c1
Reactant: O=C(O)c1ncccc1O
Product: COc1cccc(COC(=O)c2ncccc2OCc2cccc(OC)c2)c1

Procedure:
In analogy with Example 38a), 10 g of the product were obtained, as a colorless oil which was subjected to further reaction, from 8.4 g (60 mmol) of 3-hydroxypyridine-2-carboxylic acid and 3-methoxybenzyl chloride following chromatography on silica gel.
Reaction SMILES: O.[OH-].[Li+:3].[C:4]([C:6]1[CH:7]=[C:8]([C:12]2[N:13]([CH2:25][CH2:26][CH2:27][C:28]([O:30]C)=[O:29])[CH:14]=[C:15]3[C:20]=2[C:19](=[O:21])[N:18]([CH3:22])[C:17](=[O:23])[N:16]3[CH3:24])[CH:9]=[CH:10][CH:11]=1)#[N:5]>C1COCC1.O>[C:4]([C:6]1[CH:7]=[C:8]([C:12]2[N:13]([CH2:25][CH2:26][CH2:27][C:28]([O-:30])=[O:29])[CH:14]=[C:15]3[C:20]=2[C:19](=[O:21])[N:18]([CH3:22])[C:17](=[O:23])[N:16]3[CH3:24])[CH:9]=[CH:10][CH:11]=1)#[N:5].[Li+:3]
Reactant: COC(=O)CCCn1cc2c(c1-c1cccc(C#N)c1)c(=O)n(C)c(=O)n2C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cn1c(=O)c2c(-c3cccc(C#N)c3)n(CCCC(=O)[O-])cc2n(C)c1=O
Reaction time: 2 h

Procedure:
Lithium hydroxide monohydrate (1.158 g, 27.6 mmol) was added to a suspension of methyl 4-(5-(3-cyanophenyl)-1,3-dimethyl-2,4-dioxo-3,4-dihydro-1H-pyrrolo[3,4-d]pyrimidin-6(2H)-yl)butanoate (Example 9 Step 5) (10 g, 26.3 mmol) in THF (99 ml) and water (32.9 ml). The mixture was stirred for 2 hours and evaporated under vacuum to afford the title compound.
Reaction SMILES: Cl.Cl.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH2:11])[CH2:4]2.[I:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16](O)=[O:17]>>[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH:11][C:16](=[O:17])[C:15]1[CH:19]=[CH:20][CH:21]=[C:13]([I:12])[CH:14]=1)[CH2:4]2
Reactant: N[C@H]1CN2CCC1CC2
Reactant: O=C(O)c1cccc(I)c1
Agent: Cl
Product: O=C(N[C@H]1CN2CCC1CC2)c1cccc(I)c1

Procedure:
Prepared by a method analogous to that described for the preparation of Intermediate 1 from (R)-1-azabicyclo[2.2.2]oct-3-ylamine dihydrochloride and 3-iodobenzoic acid; the compound was purified by solid phase extraction on silica gel using ammoniated methanol/chloroform mixtures as the eluent followed by reverse phase HPLC on a Waters Bondapak® C18 column using a gradient of acetonitrile and 0.1% aqueous trifluoroacetic acid as the eluent. The product-containing fractions were evaporated, the residue was dissolved in methanol, excess hydrogen chloride solution (4M in 1,4-dioxane) was added and the solution was evaporated to give the hydrochloride salt of the title compound as a colourless solid; MS (ES+) 357 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][CH:7]=1.[C:15]1(B(O)O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[C:15]1([C:2]2[CH:3]=[C:4]([CH:8]=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][CH:7]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)C=Cc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C=Cc1cccc(-c2ccccc2)c1
Yield: 110.6 %

Procedure:
A stirred mixture of 11.0 grams (0.043 mole) of ethyl 3-(3-bromophenyl)-2-propenoate, 5.8 grams (0.047 mole) of phenylboronic acid, 0.25 gram (catalyst) of tetrakis-(triphenylphosphine)palladium(0), and 54.0 mL (0.110 mole) of a 2M solution of aqueous sodium carbonate in 100 mL of toluene was heated at reflux during a two hour period. After this time the reaction mixture was cooled, and the aqueous layer was separated. The toluene layer was washed with two 100 mL portions of water and then with 100 mL of an aqueous solution saturated with sodium chloride. The toluene layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 12.0 grams of ethyl 3-(3-phenylphenyl)-2-propenoate. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [OH:1][CH:2]([C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:3][N:4]1[C:9](=[O:10])[C:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)=[C:7]([CH2:26][CH2:27][CH3:28])[N:6]2[N:29]=[C:30]([CH3:32])[N:31]=[C:5]12.[H-].[Na+].[CH3:39]N(C)C=O.CI>C(OCC)(=O)C>[CH3:39][O:1][CH:2]([C:33]([CH3:35])([CH3:34])[CH3:36])[CH2:3][N:4]1[C:9](=[O:10])[C:8]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:16][CH:17]=2)=[C:7]([CH2:26][CH2:27][CH3:28])[N:6]2[N:29]=[C:30]([CH3:32])[N:31]=[C:5]12
Reactant: CN(C)C=O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(CC(O)C(C)(C)C)c2nc(C)nn12
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(CC(OC)C(C)(C)C)c2nc(C)nn12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 72 %

Procedure:
A mixture of 4′-{[4-(2-hydroxy-3,3-dimethylbutyl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.3 g), sodium hydride (0.03 g) and N,N-dimethylformamide (5 mL) was stirred at 0° C. for 10 min, methyl iodide (0.046 mL) was added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.22 g, 72%).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6]4=[C:7]([C:17](=[O:27])[C:18]([CH2:20][C:21]5[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=5)=[CH:19][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([OH:16])[CH:10]=3.Cl[CH2:29][C:30]1[NH:31][C:32]2[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=2[N:34]=1>>[N:31]1[C:32]2[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=2[NH:34][C:30]=1[CH2:29][O:16][C:9]1[CH:10]=[C:11]2[C:6]3=[C:7]([C:17](=[O:27])[C:18]([CH2:20][C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)=[CH:19][N:5]3[C:4]3[CH:3]=[C:2]([Br:1])[CH:15]=[CH:14][C:13]=3[S:12]2)[CH:8]=1
Reactant: O=c1c(Cc2cccnc2)cn2c3c(cc(O)cc13)Sc1ccc(Br)cc1-2
Reactant: ClCc1nc2ccccc2[nH]1
Product: O=c1c(Cc2cccnc2)cn2c3c(cc(OCc4nc5ccccc5[nH]4)cc13)Sc1ccc(Br)cc1-2
Yield: 1.5 %

Procedure:
According to Example 34, the compound (500 mg) produced in Example 37 was reacted with 2-chloromethylbenzimidazole (243 mg) to obtain the title compound (10 mg; 0.2%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[C:18]2[CH:23]=[CH:22][C:21](/[CH:24]=[CH:25]/[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:20][CH:19]=2)=[C:9](\[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)/[CH2:10][CH3:11])=[CH:4][CH:3]=1.CCN(CC)CC.Cl[C:41]([O:43][CH2:44][CH3:45])=[O:42]>C(Cl)Cl>[CH2:44]([O:43][C:41]([O:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[C:18]2[CH:19]=[CH:20][C:21](/[CH:24]=[CH:25]/[C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])=[CH:22][CH:23]=2)=[C:9](\[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)/[CH2:10][CH3:11])=[CH:4][CH:3]=1)=[O:42])[CH3:45]
Reactant: CC/C(=C(/c1ccc(O)cc1)c1ccc(/C=C/C(=O)OC(C)(C)C)cc1)c1ccccc1
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)Oc1ccc(/C(=C(/CC)c2ccccc2)c2ccc(/C=C/C(=O)OC(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.4 %

Procedure:
To a solution of tert-butyl ester 12 (0.45 g, 1.06 mmol) in CH2Cl2 (20 mL) at 0° C. was added Et3N (0.32 mL, 0.23 g, 2.33 mmol) and ethyl chloroformate (0.115 mL, 0.126 g, 1.16 mmol) and the mixture stirred at ambient temperature for 1 h. The mixture was washed with ice-chilled 0.1 N hydrochloric acid and the organic layer dried (Na2SO4) and evaporated to provide compound 39 as an off-white solid (0.52 g, 99%); 1H NMR (DMSO-d6): δ 0.86 (t, J=7.1 Hz, 3H), 1.23 (t, J=7.5 Hz, 3H), 1.48 (s, 9H), 2.40 (q, J=7.5 Hz, 2H), 4.17 (q, J=7.1 Hz, 2H), 6.51 (d, J=16 Hz, 1H), 6.87 (d, J=9 Hz, 2H), 6.91 (d, J=9 Hz, 2H), 7.10-7.16 (m, 3H), 7.18-7.22 (m, 2H), 7.25 (d, J=8.1 Hz, 2H), 7.55 (d, J=16 Hz, 1H), 7.71 (d, J=8.1 Hz, 2H); MS, m/z 521 (M+Na)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[CH:9][N:8]([CH:24]3[CH2:29][CH2:28][CH:27]([CH2:30][CH:31]=O)[CH2:26][CH2:25]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:33][N:34]1[CH2:39][CH2:38][N:37]([CH2:31][CH2:30][CH:27]2[CH2:28][CH2:29][CH:24]([N:8]3[C:4]4[N:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]=4[C:10]([C:11]4[CH:16]=[CH:15][C:14]([O:17][C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=5)=[CH:13][CH:12]=4)=[CH:9]3)[CH2:25][CH2:26]2)[CH2:36][CH2:35]1
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)cn2C1CCC(CC=O)CC1
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CN1CCN(CCC2CCC(n3cc(-c4ccc(Oc5ccccc5)cc4)c4c(N)ncnc43)CC2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 52.5 %

Procedure:
A mixture of 2-{4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexyl}acetaldehyde (0.025 g, 0.059 mmol), N-methylpiperazine (0.0083 g, 0.083 mmol) and acetic acid (0.0035 g, 0.059 mmol) in 1,2-dichloroethane (0.4 mL) was stirred for 10 min at ambient temperature and sodium triacetoxyborohydride (0.019 g, 0.089 mmol) was added. The mixture was stirred at ambient temperature under an atmosphere of nitrogen for 6 hours and the solvent removed under reduced to yield a yellow oil. The compound was purified by preparative RP-HPLC to yield 7-{4-[2-(4-methylpiperazino)ethyl]cyclohexyl}-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.016 g, 0.031 mmol) as a white solid: 1H NMR (CDCl3, 400 MHz) δ 8.27(s, 1H), 7.45(d, 2H), 7.37(t, 2H), 7.16(t, 1H), 7.09(m, 5H), 5.57(br, 2H), 4.73(m, 1H), 2.33(s, 3H), 2.49-1.65(m, 19H); RP-HPLC (Hypersil C18, 5 μm, 100 A, 250×4.6 mm; 25%-100% acetonitrile-0.05M ammonium acetate over 10 min, 1 mL/min) Rt 8.15 min. MS: MH+ 511.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[CH:4]=1.[C:10]1([CH:16]([C:22](OCC)=[O:23])[C:17](OCC)=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1(OC2C=CC=CC=2)C=CC=CC=1>[C:10]1([C:16]2[C:17](=[O:18])[NH:9][C:5]3[C:6]([C:22]=2[OH:23])=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COc1cccc(N)c1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccccc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COc1ccc2c(O)c(-c3ccccc3)c(=O)[nH]c2c1
Temperature: 25 °C
Yield: 91.9 %

Procedure:
A dark solution of 3-anisidine (5.37 g, 44.8 mmol), diethyl 2-phenylmalonate (10.57 g, 44.8 mmol), and diphenyl ether (50 mL) was heated at 220° C. for 1 h without a reflux condenser to allow ethanol evaporation. The reaction was cooled to rt, and the resultant gray precipitate filtered and washed with diethyl ether and dried to afford 11.0 g 2a (R2=7-OMe in Scheme 1, 92% yield): MS (M+H)+ 269.28.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([S:21](Cl)(=[O:23])=[O:22])[CH:18]=[CH:19][CH:20]=1>>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([S:21]([NH:1][C:2]2[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)(=[O:23])=[O:22])[CH:18]=[CH:19][CH:20]=1
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: COc1cccc(S(=O)(=O)Cl)c1
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2cccc(OC)c2)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 3-methoxybenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (18.6 mg) with purity >90%. LCMS (pos) m/z 357.0.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH:10]=[CH:11]OC.[ClH:14].[NH:15]([C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1)[NH2:16].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[ClH:14].[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH2:10][CH:11]=[N:16][NH:15][C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1
Reactant: COC=Cc1cc(OC)ccc1F
Reactant: NNc1ccncc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCO
Product: COc1ccc(F)c(CC=NNc2ccncc2)c1
Yield: 40.8 %

Procedure:
To a solution of 1-fluoro-4-methoxy-2-(2-methoxyvinyl)benzene (20 g) and 4-hydrazinopyridine hydrochloride (17.7 g) in ethanol (300 ml), p-toluene sulfonic acid (3.13 g) was added, with stirring. The reaction mixture was stirred under reflux for 2 hrs, filtered, and the filtrate was concentrated in vacuo. The residue was recrystallized from methanol to yield 13.24 g (41%) of product, mp 219-220° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:17]1[C:25]2[C:20](=[CH:21][C:22]([S:26]([N:29](CC3C=CC(OC)=CC=3OC)[C:30]3[S:34][N:33]=[CH:32][N:31]=3)(=[O:28])=[O:27])=[CH:23][CH:24]=2)[N:19]([CH3:46])[CH:18]=1>>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:17]2[C:25]3[C:20](=[CH:21][C:22]([S:26]([NH:29][C:30]4[S:34][N:33]=[CH:32][N:31]=4)(=[O:27])=[O:28])=[CH:23][CH:24]=3)[N:19]([CH3:46])[CH:18]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(B(O)O)c2ccccc12
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(Br)cn(C)c3c2)c(OC)c1
Product: COc1ccc(-c2cn(C)c3cc(S(=O)(=O)Nc4ncns4)ccc23)c2ccccc12

Procedure:
The title compound was prepared in an analogous manner to that described in Example 28 using (4-methoxynaphthalen-1-yl)boronic acid and 3-bromo-N-(2,4-dimethoxybenzyl)-1-methyl-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide, and the desired product, 3-(4-methoxynaphthalen-1-yl)-1-methyl-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide, was isolated as an off-white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 3.96 (s, 3 H) 4.02 (s, 3 H) 7.06 (d, J=8.02 Hz, 1 H) 7.32 (d, J=8.36 Hz, 1 H) 7.37-7.48 (m, 3 H) 7.51 (d, J=8.25 Hz, 1 H) 7.72 (s, 1 H) 7.84 (d, J=8.59 Hz, 1 H) 7.97 (s, 1 H) 8.13 (s, 1 H) 8.24 (d, J=8.36 Hz, 1 H). m/z (ESI) 450.1 (M+H)+.
Reaction SMILES: C(C1CCC([N:11]([CH2:26][C:27]2[CH:44]=[CH:43][C:30]([C:31]([CH:33]([NH:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41])[CH:34]3[CH2:36][CH2:35]3)=[O:32])=[CH:29][CH:28]=2)[C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)=[O:13])CC1)(C)(C)C.[C:45](O)([C:47](F)(F)F)=O>ClCCl>[C:27]([CH:45]1[CH2:47][CH2:17][CH:16]([CH:26]([NH:11][C:12]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][C:22]([F:23])([F:24])[F:25])=[CH:19][CH:20]=2)=[O:13])[C:27]2[CH:44]=[CH:43][C:30]([C:31]([CH:33]([NH:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41])[CH:34]3[CH2:35][CH2:36]3)=[O:32])=[CH:29][CH:28]=2)[CH2:15][CH2:20]1)([CH3:44])([CH3:28])[CH3:26]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)C1CCC(N(Cc2ccc(C(=O)C(NCCC(=O)O)C3CC3)cc2)C(=O)Nc2ccc(OC(F)(F)F)cc2)CC1
Solvent: ClCCl
Product: CC(C)(C)C1CCC(C(NC(=O)Nc2ccc(OC(F)(F)F)cc2)c2ccc(C(=O)C(NCCC(=O)O)C3CC3)cc2)CC1
Reaction time: 0.08 h

Procedure:
The above resin bound 3-({4-[1-(4-tert-butylcyclohexyl)-3-(4-trifluoromethoxyphenyl)-ureidomethyl]benzoyl}cyclopropylmethyl)aminopropionic acid (50 mg) was treated with 1 mL 5% TFA in dichloromethane for 1 hour at 25° C. The product was filtered off and the resin was washed with 1 mL dichloromethane. The combined extracts were concentrated in vacuo. The residue was dissolved in 50 μL DMSO+500 μL acetonitrile and purified by preparative HPLC using a Supelcosil ABZ+25 cm×10 mm 5μ column. The starting eluent composition was 5% acetonitrile in water changing over 30 min to 90% acetonitrile in water which was then kept constant for 5 min before going back to the starting composition over 10 min. The flow rate was kept constant at 8 mL/min collecting one fraction per minute. The process was monitored using an UV detector operating at 214 nm. The fractions containing the desired product were combined and evaporated in vacuo to afford the title compound.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[O:57]=[C:58]1[CH:62]([C:63](O)=[O:64])[CH2:61][CH2:60][N:59]1[C:66]1[CH:71]=[CH:70][C:69]([CH3:72])=[CH:68][CH:67]=1>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:63]([CH:62]1[CH2:61][CH2:60][N:59]([C:66]2[CH:71]=[CH:70][C:69]([CH3:72])=[CH:68][CH:67]=2)[C:58]1=[O:57])=[O:64]
Reactant: Cc1ccc(N2CCC(C(=O)O)C2=O)cc1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(N2CCC(C(=O)NCCc3c[nH]c4ccc(Cl)cc34)C2=O)cc1
Yield: 42.1 %

Procedure:
This compound was prepared according to method E with 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0200 g; 0.865 mmol), PyBOP (0.450 g; 0.865 mmol), N,N diisopropylethylamine (0.373 mL; 2.16 mmol) and 2-oxo-1-p-tolylpyrrolidine-3-carboxylic acid (0.189 g; 0.865 mmol) in DMF (3 mL). The crude mixture was purified flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.144 g (42%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2-oxo-1-p-tolylpyrrolidine-3-carboxamide as a white solid.
Reaction SMILES: [CH3:1][NH:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[Cl-].[N-:21]=[N+:22]=[N-:23].[Na+]>CN(C=O)C.CCOC(C)=O>[CH3:1][N:2]1[C:3]([C:4]2[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=2)=[N:23][N:22]=[N:21]1
Reactant: CNC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: [N-]=[N+]=[N-]
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1nnnc1-c1ccc([N+](=O)[O-])cc1
Temperature: 130 °C
Reaction time: 8 h

Procedure:
N-Methyl-4-nitro-benzamide (2.25 g, 12.5 mmol, 1 eq.) and PCl5 (2.60 g, 12.5 mmol, 1 eq.) were melted together under house vacuum connected to a NaOH trap behind a safety shield. Melting occurred at 100° C. Heated at 130° C. for 1 hour then purified by kugelrohr distillation at 0.1 mmHg at 130° C. CAUTION: THE EXPLOSIVE PROPERTIES OF THIS COMPOUND ARE UNKNOWN). The iminoyl chloride (12.5 mmol 1 eq.) in DMF 10 ml was added to NaN3 in 10 ml of DMF at 25° C. and stirred overnight. Worked up by adding EtOAc then rinsing 3× with H20. The organic layer was dried over MgSO4, then stripped to obtain yellow solids which were purified over silica gel in 3:1 hexanes/EtOAc to 100% EtOAc. Obtained 1.21 g of yellow solids as product. NMR (300 MHz, CDCl3) δ 8.46 (d, 2H, J=7 Hz), 8.02 (d, 2H, J=7 Hz),4.27 (s, 3H).
Reaction SMILES: C([O:8][C:9](=[O:47])[CH2:10][N:11]([S:40]([CH2:43][CH2:44][CH2:45][CH3:46])(=[O:42])=[O:41])[C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:23][CH2:22][CH:21]([NH:24][CH2:25][C@H:26]([OH:39])[C:27]3[CH:32]=[CH:31][C:30]([OH:33])=[C:29]([NH:34][S:35]([CH3:38])(=[O:37])=[O:36])[CH:28]=3)[CH2:20][CH2:19]2)=[CH:14][CH:13]=1)C1C=CC=CC=1>[Pd].CO>[CH2:43]([S:40]([N:11]([CH2:10][C:9]([OH:47])=[O:8])[C:12]1[CH:13]=[CH:14][C:15]([N:18]2[CH2:19][CH2:20][CH:21]([NH:24][CH2:25][C@H:26]([OH:39])[C:27]3[CH:32]=[CH:31][C:30]([OH:33])=[C:29]([NH:34][S:35]([CH3:38])(=[O:37])=[O:36])[CH:28]=3)[CH2:22][CH2:23]2)=[CH:16][CH:17]=1)(=[O:42])=[O:41])[CH2:44][CH2:45][CH3:46]
Reactant: CCCCS(=O)(=O)N(CC(=O)OCc1ccccc1)c1ccc(N2CCC(NC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1
Agent: [Pd]
Solvent: CO
Product: CCCCS(=O)(=O)N(CC(=O)O)c1ccc(N2CCC(NC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1
Reaction time: 8 h

Procedure:
A mixture of 0.18 g of [(butane-1-sulfonyl)-(4-{4-[(2R)-2-hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidine-1-yl}-phenyl)-amino]-acetic acid benzyl ester (which was obtained in Example 342) and 0.05 g of 10% palladium on carbon in 15 mL of methanol was shaken on a Parr hydrogenator at 25 psi overnight. The mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo, which afforded a beige solid; 1H NMR (300 MHz, DMSO-d6) δ 0.86 (t, J=7.23 Hz, 3H), 1.29-1.41 (m, 2H), 1.48-1.51 (m, 2H), 1.54-1.73 (m, 2H), 1.92-2.09 (m, 2H), 2.57-2.64 (m, 2H), 2.79-2.87 (m, 2H), 2.94 (s, 3H), 3.00-3.07 (m, 4H), 3.16 (s, 2H), 3.20-3.26 (m, 2H), 3.64-3.75 (m, 2H), 4.02-4.04 (m, 2H), 4.77-4.81 (m,1H), 6.84-6.91 (m, 3H), 7.06 (dd, J=2.1 Hz, 8.4 Hz, 2H), 7.23 (d, J=1.8 Hz,1H), 7.34 (d, J=9.00 Hz, 2H); MS (ES) m/z: 599.0 (MH+); HRMS found for C26H38N4O8S2: 599.2202.