Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@H:2]1[N:7]([C:8]2[C:9]3[CH2:24][CH2:23][N:22]([C:25]4[N:30]=[CH:29][CH:28]=[CH:27][N:26]=4)[CH2:21][C:10]=3[N:11]=[C:12]([C:14]3[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=3)[N:13]=2)[CH2:6][CH2:5][O:4][CH2:3]1.[O:31]1[CH2:36]COCC1.C(N(CC)CC)C.C(Cl)(Cl)=O.[F:48][CH2:49][CH2:50][NH2:51]>C1(C)C=CC=CC=1>[F:48][CH2:49][CH2:50][NH:51][C:36]([NH:18][C:17]1[CH:19]=[CH:20][C:14]([C:12]2[N:13]=[C:8]([N:7]3[CH2:6][CH2:5][O:4][CH2:3][C@@H:2]3[CH3:1])[C:9]3[CH2:24][CH2:23][N:22]([C:25]4[N:26]=[CH:27][CH:28]=[CH:29][N:30]=4)[CH2:21][C:10]=3[N:11]=2)=[CH:15][CH:16]=1)=[O:31]
Reactant: NCCF
Reactant: C1COCCO1
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(N)cc2)nc2c1CCN(c1ncccn1)C2
Agent: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NCCF)cc2)nc2c1CCN(c1ncccn1)C2
Temperature: 50 °C
Reaction time: 72 h

Procedure:
(S)-4-(4-(3-methylmorpholino)-7-(pyrimidin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)aniline (0.0501 g, 0.000124 mol) in dry 1,4-Dioxane (2.00 mL, 0.0256 mol) was added Triethylamine (0.0190 mL, 0.000136 mol) followed by 20% Phosgene in toluene (1:4, Phosgene:Toluene, 0.080 mL). The reaction mixture was heated at 50° C. for 1 hour. The reaction mixture was cooled to room temperature and then added 2-fluoroethanamine (0.0534 g, 0.000762 mol) followed by Triethylamine (0.1140 mL, 0.0008179 mol). The reaction mixture was stirred for 3 days. The reaction mixture was concentrated and purified by HPLC. LC/MS-m/z+493.2 (M+H)+
Reaction SMILES: [NH2:1][C@H:2]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)[C:3]([N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH2:7][CH2:6]1)=[O:4].CCN(C(C)C)C(C)C.[N:39]1([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:46][CH2:45][CH2:44][C@H:40]1[C:41](O)=[O:42].C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][C@@H:2]([NH:1][C:41]([C@@H:40]2[CH2:44][CH2:45][CH2:46][N:39]2[C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])=[O:42])[C:3]([N:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[NH:17][S:18]([CH3:21])(=[O:19])=[O:20])[CH2:7][CH2:6]2)=[O:4])=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: CS(=O)(=O)Nc1ccccc1C1CCN(C(=O)[C@H](N)Cc2ccc(Cl)cc2)CC1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCC(c2ccccc2NS(C)(=O)=O)CC1
Yield: 67.6 %

Procedure:
The title compound was prepared according to the procedure described in Example 1, Step (f) using (2R)-2-amino-3-(4-chlorophenyl)-1-(4-{2-[(methylsulfonyl)-amino]phenyl}piperidyl)propan-1-one (Example 1, Step g) (471 mg, 1.0 mmol), DIEA (Aldrich) (0.20 mL, 1.0 mmol), Boc-ProOH (Fisher Scientific) (323 mg, 1.5 mmol), HOAT (Aldrich) (232 mg, 1.70 mmol) and EDC (Aldrich) (544 mg, 2.84 mmol) in DMF (10 mL). Purification by silica gel chromatography (100% EtOAc) provided the title compound as a white foam (428 mg). MS (ESI, pos. ion) m/z: 633 (M+1); (ESI, neg. ion) m/z: 631 (M−1). Calc'd for C31H41ClN4O6S: 633.20.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][N:26]([CH3:28])[CH3:27])=[CH:20][CH:19]=1.[Cl:29][C:30]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[C:32]([Cl:45])[C:31]=1[OH:46]>>[ClH:29].[ClH:29].[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[NH:17][C:18]2[CH:19]=[CH:20][C:21]([CH2:24][CH2:25][N:26]([CH3:28])[CH3:27])=[CH:22][CH:23]=2)=[CH:3][C:2]([C:34]2[CH:35]=[C:30]([Cl:29])[C:31]([OH:46])=[C:32]([Cl:45])[CH:33]=2)=[CH:11][CH:10]=3)=[O:13])[CH2:16][CH2:15]1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Reactant: CN(C)CCc1ccc(Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)cc1
Product: CN(C)CCc1ccc(Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(Cl)c(O)c(Cl)c4)cc23)cc1
Product: Cl

Procedure:
Following general procedure D, (6-bromo-4-(4-(2-(dimethylamino)ethyl)phenylamino)quinolin-3-yl)(cyclopropyl)methanone (7.3 g, 16.7 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (5.6 g, 20 mol) to obtain the desired product which was dissolved methanol and treated with excess 1 N aq. HCl. During removal of the methanol via rotary evaporation a precipitate appeared which was filtered to obtain the desired product (5.6 g, 64% over 2 steps) as a yellow solid: 1H NMR (300 MHz, MeOD) δ 9.46 (s, 1H), 8.21 (dd, J=8.8, 1.9 Hz, 1H), 8.01 (d, J=8.8 Hz, 1H), 7.89 (s, 1H), 7.57 (d, J=9 Hz, 2H), 7.46 (d, J=9 Hz, 2H), 7.23 (s, 2H), 3.40 (m, 2H), 3.22 (m, 2H), 2.98 (s, 7H), 2.90 (t, J=4.8 Hz, 1H), 1.22 (m, 4H); ESI MS m/z 520 [C29H27Cl2N3O2+H]+; HPLC 99.1% (AUC), tR=10.54 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[C:9](OC(=O)C)(=[O:11])[CH3:10].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl>[C:9](=[O:11])([S:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1])[CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: Sc1ccccc1Br
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Sc1ccccc1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A stirred solution of 2-bromothiophenol (100 g, 0.529 mol), acetic anhydride (62.4 mL, 0.661 mol), and 4-dimethylaminopyridine (3.2 g, 0.026 mol) in dichloromethane (1000 mL) was cooled in an ice-bath. Triethylamine (92.2 mL, 0.662 mol) was slowly added, and then the ice bath was removed. The mixture was stirred at room temperature for 1 hour. Water (10 mL) was added, and after a couple of minutes the mixture was washed with aqueous 1N hydrochloric acid (3×300 mL), 10% sodium hydroxide solution (3×300 mL), and 1N hydrochloric acid (300 mL), and then dried (Na2SO4), and filtered. Evaporation of the solvent left S-2-bromophenyl ethanethioate as a pale yellow oil (104 g).
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]([O:6][C@@H:7]2[CH2:11][CH2:10][CH2:9][C@@H:8]2[NH:12][S:13]([CH:16]([CH3:18])[CH3:17])(=[O:15])=[O:14])=[CH:4][CH:3]=1.[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O)#[N:22].C1(B(O)O)C=CC=CC=1>>[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:2]1[CH:20]=[CH:19][C:5]([O:6][C@@H:7]2[CH2:11][CH2:10][CH2:9][C@@H:8]2[NH:12][S:13]([CH:16]([CH3:18])[CH3:17])(=[O:15])=[O:14])=[CH:4][CH:3]=1)#[N:22]
Reactant: CC(C)S(=O)(=O)N[C@H]1CCC[C@H]1Oc1ccc(Br)cc1
Reactant: N#Cc1ccccc1B(O)O
Agent: OB(O)c1ccccc1
Product: CC(C)S(=O)(=O)N[C@H]1CCC[C@H]1Oc1ccc(-c2ccccc2C#N)cc1

Procedure:
The title compound of Step 7 was prepared according to the general procedure for the synthesis of Example 2, except that N-[(1S,2R)-2-(4-bromophenoxy)cyclopentyl]propane-2-sulfonamide was used instead of N-[(3S,4S)-4-(4-bromophenoxy)tetrahydrofuran-3-yl]propane-2-sulfonamide, and (2-cyanophenyl)boronic acid was added in place of phenylboronic acid. After the reaction mixture was concentrated in vacuo, it was directly purified by silica gel chromatography in this case (Eluant: 25% ethyl acetate in heptane), to afford the product as a sticky white foam. Trituration with hexanes gave product as a white powder. Yield: 53 mg, 0.14 mmol, 82%. MS (APCI) m/z 382.9 (M−1). 1H NMR (400 MHz, CDCl3) δ 1.36 (d, J=6.7 Hz, 3H), 1.40 (d, J=6.8 Hz, 3H), 1.66 (m, 1H), 1.82-2.03 (m, 4H), 2.15 (m, 1H), 3.15 (septet, J=6.8 Hz, 1H), 3.90 (m, 1H), 4.70 (m, 2H), 7.01 (d, J=8.8 Hz, 2H), 7.42 (ddd, J=7.6, 7.6, 1.2 Hz, 1H), 7.50 (m, 1H), 7.52 (d, J=8.8 Hz, 2H), 7.64 (ddd, J=7.7, 7.7, 1.4 Hz, 1H), 7.76 (m, 1H).
Reaction SMILES: [CH3:1][CH:2]([CH3:35])[CH2:3][O:4][C:5](=[O:34])[CH2:6][NH:7][C:8](=[O:33])[C@H:9]([CH2:17][N:18]1[CH2:23][CH2:22][C@:21]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[CH:26]=2)([CH3:24])[C@@H:20]([CH3:32])[CH2:19]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C:36]([OH:44])(=[O:43])[C@H:37]([CH2:39][C:40]([OH:42])=[O:41])[OH:38].[CH3:45]C(C)=O>C(OCC)(=O)C>[C:36]([OH:44])(=[O:43])[CH:37]([CH2:39][C:40]([OH:42])=[O:41])[OH:38].[CH3:45][CH:3]([O:4][C:5](=[O:34])[CH2:6][NH:7][C:8](=[O:33])[C@H:9]([CH2:17][N:18]1[CH2:23][CH2:22][C@:21]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[CH:26]=2)([CH3:24])[C@@H:20]([CH3:32])[CH2:19]1)[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH2:2][CH3:1].[C:36]([OH:44])(=[O:43])[CH:37]([CH2:39][C:40]([OH:42])=[O:41])[OH:38].[C:36]([OH:44])(=[O:43])[CH:37]([CH2:39][C:40]([OH:42])=[O:41])[OH:38].[OH:31][C:27]1[CH:26]=[C:25]([C@:21]2([CH3:24])[CH2:22][CH2:23][N:18]([CH2:17][C@H:9]([CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:8]([NH:7][CH2:6][C:5]([O:4][CH:3]([CH3:36])[CH2:2][CH3:35])=[O:34])=[O:33])[CH2:19][C@@H:20]2[CH3:32])[CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)COC(=O)CNC(=O)[C@@H](Cc1ccccc1)CN1CC[C@@](C)(c2cccc(O)c2)[C@@H](C)C1
Reactant: CC(C)=O
Reactant: O=C(O)C[C@H](O)C(=O)O
Solvent: CCOC(C)=O
Product: CCC(C)OC(=O)CNC(=O)[C@@H](Cc1ccccc1)CN1CC[C@@](C)(c2cccc(O)c2)[C@@H](C)C1
Product: O=C(O)CC(O)C(=O)O
Temperature: 70 °C

Procedure:
A compound of Example 1, (2.5 g, 5.2 mmol, 1.0 equiv) was dissolved in 50 mL of ethyl acetate. L-malic acid (1.03 g, 7.8 mmol, 1.5 eq) was added to the mixture. After the L-malic acid was dissolved by stirring, the solution was heated to 70° C. and 4.0 mL of acetone was added. The solution was crystallized. The product was isolated by filtration. The filter cake was washed with ethyl acetate. The salt was dried until the ethyl acetate levels were below 1%. The title compound was isolated as a white crystal. The sample was analyzed using x-ray powder diffraction. mp 94°-950C.
Reaction SMILES: COP([CH2:7][C:8]1[S:16][C:15]2[C:14]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[N:13][C:12]([Cl:23])=[N:11][C:10]=2[CH:9]=1)(=O)OC.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:34]([O:38][C:39]([N:41]1[CH2:44][C:43](=O)[CH2:42]1)=[O:40])([CH3:37])([CH3:36])[CH3:35]>C1COCC1>[C:34]([O:38][C:39]([N:41]1[CH2:44][C:43](=[CH:7][C:8]2[S:16][C:15]3[C:14]([N:17]4[CH2:18][CH2:19][O:20][CH2:21][CH2:22]4)=[N:13][C:12]([Cl:23])=[N:11][C:10]=3[CH:9]=2)[CH2:42]1)=[O:40])([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: COP(=O)(Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1)OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(=Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)C1
Reaction time: 0.5 h
Yield: 63.7 %

Procedure:
To a suspension of (2-chloro-4-morpholin-4-ylthieno[3,2-d]pyrimidin-6-ylmethyl)phosphonic acid dimethyl ester (3.0 g, 7.94 mmol) in THF (150 mL) at −78° C. was added LiHMDS (8.8 mL, 8.80 mmol, 1M solution in THF) and the resulting mixture stirred for 30 min then warmed to r.t. before the addition of a solution of 3-oxo-azetidine-1-carboxylic acid tert-butyl ester (1.51 g, 8.82 mmol) in THF (20 mL). The reaction mixture was stirred at r.t. for 16 h then quenched with H2O and MeOH and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, EtOAc:DCM, 5-100%) affording the title compound as a yellow solid (2.14 g, 63%). LCMS (method A): RT 3.97 min [M+H]+ 423.3
Reaction SMILES: [CH2:1]([S:3]([C:6]1[N:7]=[CH:8][N:9]2[CH:13]=[CH:12][S:11][C:10]=12)(=[O:5])=[O:4])[CH3:2].C([Li])CCC.CCCCCC.[CH2:25]([Sn:29](Cl)([CH2:34][CH2:35][CH2:36][CH3:37])[CH2:30][CH2:31][CH2:32][CH3:33])[CH2:26][CH2:27][CH3:28].[Cl-].[NH4+]>C1COCC1>[CH2:1]([S:3]([C:6]1[N:7]=[CH:8][N:9]2[CH:13]=[C:12]([Sn:29]([CH2:30][CH2:31][CH2:32][CH3:33])([CH2:34][CH2:35][CH2:36][CH3:37])[CH2:25][CH2:26][CH2:27][CH3:28])[S:11][C:10]=12)(=[O:4])=[O:5])[CH3:2]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: CCS(=O)(=O)c1ncn2ccsc12
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(S(=O)(=O)CC)c2s1
Reaction time: 0.25 h

Procedure:
A solution of 669 mg of 7-ethanesulfonylimidazo[5,1-b]thiazole in 30 ml of THF was cooled to −40° C. in an argon atmosphere. A 1.6 N n-butyllithium/n-hexane solution (4.3 ml) was added dropwise thereto at the same temperature. The mixture was stirred for 15 min. Tri-n-butylstannyl chloride (0.88 ml) was added thereto, followed by stirring at the same temperature for 10 min. A saturated aqueous ammonium chloride solution was added thereto. The mixture was extracted twice with ethyl acetate. The extract was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:1). The title compound (1.54 g) was obtained from the fraction of Rf=0.2.
Reaction SMILES: S(=O)(=O)(O)O.[CH:6]([N:9]1[CH2:12][CH:11]([C:13]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:14]#[N:15])[CH2:10]1)([CH3:8])[CH3:7].[OH-:28].[Na+]>>[C:16]1([C:13]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([CH:11]2[CH2:12][N:9]([CH:6]([CH3:8])[CH3:7])[CH2:10]2)[C:14]([NH2:15])=[O:28])[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)N1CC(C(C#N)(c2ccccc2)c2ccccc2)C1
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CC(C)N1CC(C(C(N)=O)(c2ccccc2)c2ccccc2)C1
Temperature: 70 °C

Procedure:
To 80 ml. of concentrated sulfuric acid preheated to 70° C. was added 25 g. (0.86 mole) of α-(1-isopropyl-3-azetidinyl)-α,α-diphenylacetonitrile at a rate to maintain a temperature of 65°-75° C. The solution was heated at 70° C. for 18 hrs. and poured on ice. The mixture was made basic with 50% sodium hydroxide (while cooling with ice) and extracted with chloroform. The chloroform was dried (sodium sulfate) and concentrated. The residue was crystallized from ethyl acetate-ethanol to give 15.7 g. (59%) of product melting at 181°-184° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1.[CH:12]1([C:15](Cl)=[O:16])[CH2:14][CH2:13]1.N1C=CC=CC=1>CCOCC>[CH:12]1([C:15]([O:11][CH2:10][CH2:9][S:8][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[O:16])[CH2:14][CH2:13]1
Reactant: O=C(Cl)C1CC1
Reactant: OCCSc1ccc(Cl)cc1
Solvent: CCOCC
Solvent: c1ccncc1
Product: O=C(OCCSc1ccc(Cl)cc1)C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 1.88 g. 2-(4-chlorophenylthio)ethanol and 1.35 g. cyclopropylcarboxylic acid chloride in 50 ml. ether is added 2 equivalents pyridine. The reaction mixture is stirred overnight at room temperature and worked up as in Example 5 to yield 2-(4-chlorophenylthio)ethyl cyclopropanecarboxylate.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.C(N(CC)CC)C.[F:25][C:26]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:27]=1[CH:28]=[CH:29][C:30](O)=[O:31].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[F:25][C:26]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:27]=1[CH:28]=[CH:29][C:30]([NH:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=[O:31]
Reactant: O=C(O)C=Cc1cc(F)ccc1F
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)C=Cc1cc(F)ccc1F
Yield: 90.6 %

Procedure:
The same procedures as in Example 2 were carried out from methyl L-tryptophanate hydrochloride (3.0 g), triethylamine (2.0 mL), 2,5-difluorocinnamic acid (2.6 g), WSC.HCl (2.7 g), and methylene chloride (80 mL), to give the captioned compound (4.1 g, 90%) as an oily product.
Reaction SMILES: [CH:1]([C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][N:9]=2)=[CH:5][CH:4]=1)=[O:2].S(=O)(=O)([OH:20])N.Cl([O-])=O.[Na+]>CC(C)=O.O.O>[C:12]([C:11]1[CH:14]=[CH:15][C:8]([O:7][C:6]2[CH:16]=[CH:17][C:3]([C:1]([OH:20])=[O:2])=[CH:4][CH:5]=2)=[N:9][CH:10]=1)#[N:13]
Reactant: N#Cc1ccc(Oc2ccc(C=O)cc2)nc1
Reactant: NS(=O)(=O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC(C)=O
Product: N#Cc1ccc(Oc2ccc(C(=O)O)cc2)nc1
Temperature: 0 °C
Yield: 86.9 %

Procedure:
6-(4-formyl-phenoxy)-nicotinonitrile (310 mg, 1.38 mmol) was dissolved in acetone-water mixture (3.5:3) (6.5 mL) and cooled to 0° C. Sulphamic acid (403 mg, 4.15 mmol) and sodium chlorite (499 mg, 5.52 mmol) dissolved in minimum amount of water were added and the resulting mixture was stirred at room temperature for half an hour. The reaction mixture was then diluted with water and extracted with ethyl acetate. The organic layer was washed with brine solution, dried over sodium sulphate and concentrated to afford 288 mg 4-(5-cyano-pyridin-2-yloxy)-benzoic acid, (85.2% yield). LCMS Purity: 83.2%,
Reaction SMILES: [CH3:1][N:2]([CH3:5])[CH2:3][CH3:4].[F:6][C:7]([F:13])([F:12])[S:8]([OH:11])(=[O:10])=[O:9]>>[F:6][C:7]([F:13])([F:12])[S:8]([O-:11])(=[O:10])=[O:9].[CH3:1][NH+:2]([CH3:5])[CH2:3][CH3:4]
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: CCN(C)C
Product: CC[NH+](C)C
Product: O=S(=O)([O-])C(F)(F)F

Procedure:
Equimolar amounts of dimethylethylamine and trifluoromethanesulfonic acid were weighed in a glove box under argon atmosphere. The weighed dimethylethylamine and trifluoromethanesulfonic acid were mixed and stirred while being cooled by liquid nitrogen, thus obtaining a target ionic conductor.
Reaction SMILES: C[O:2][C:3](=[O:16])[CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:12]([SH:15])=[C:11]2[C:7]=1[CH2:8][CH2:9][CH2:10]2.ClCC1(F)C=CC(OCC2C=CC=CC=2)=C(F)C1.O[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([OH:43])=[CH:39][CH:38]=1.Br[CH2:45][C:46]1[CH:51]=[CH:50][C:49]([F:52])=[CH:48][C:47]=1[F:53].ClCC1(C(F)(F)F)C=CC(OCC2C=CC=CC=2)=CC1>>[F:53][C:47]1[CH:48]=[C:49]([F:52])[CH:50]=[CH:51][C:46]=1[CH2:45][O:43][C:40]1[CH:41]=[CH:42][C:37]([CH2:36][S:15][C:12]2[CH:13]=[CH:14][C:6]([O:5][CH2:4][C:3]([OH:2])=[O:16])=[C:7]3[C:11]=2[CH2:10][CH2:9][CH2:8]3)=[CH:38][CH:39]=1
Reactant: COC(=O)COc1ccc(S)c2c1CCC2
Reactant: OCc1ccc(O)cc1
Reactant: Fc1ccc(CBr)c(F)c1
Agent: FC(F)(F)C1(CCl)C=CC(OCc2ccccc2)=CC1
Agent: FC1=C(OCc2ccccc2)C=CC(F)(CCl)C1
Product: O=C(O)COc1ccc(SCc2ccc(OCc3ccc(F)cc3F)cc2)c2c1CCC2

Procedure:
The title compound was prepared in the manner analogous to Example 1F using 12C and 4-chloromethyl-(2,4-difluoro-benzyloxy-benzene) prepared from 4-hydroxymethyl-phenol and 1-bromomethyl-2,4-difluoro-benzene in the manner analagous to Examples 14A and 14B. MS m/z 471 (M+1).
Reaction SMILES: [OH:1][C:2]1([CH2:8][CH2:9][N:10]2[C:14](=[O:15])[CH2:13][S:12][CH:11]2[CH2:16][CH2:17][CH2:18][C:19]2[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[C:28](=O)([O-])[O-].[K+].[K+].CI.O>CN(C)C=O>[OH:1][C:2]1([CH2:8][CH2:9][N:10]2[C:14](=[O:15])[CH2:13][S:12][CH:11]2[CH2:16][CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([C:23]([O:25][CH3:28])=[O:24])=[CH:26][CH:27]=2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: O=C(O)c1ccc(CCCC2SCC(=O)N2CCC2(O)CCCCC2)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CCCC2SCC(=O)N2CCC2(O)CCCCC2)cc1
Temperature: 25 °C
Reaction time: 19.5 h
Yield: 101.6 %

Procedure:
To a freshly-prepared solution of (±)-4-{3-[3-[2-(1-hydroxycyclohexyl)ethyl]-4-oxo-2-thiazolidinyl]propyl}benzoic acid (1) (10 g, 25.6 mmol) in dry N,N-dimethylformamide (86 ml) contained in a 250 ml round bottom flask is added finely-ground potassium carbonate (3.54 g, 25.6 mmol) followed by methyl iodide (1.6 ml, 25.6 mmol). The resulting suspension is protected from atmospheric moisture with a magnesium sulfate drying tube and is stirred at room temperature for 19.5 hours. The reaction mixture is poured into water (175 ml) contained in a separatory funnel and then is extracted with ether (3×40 ml). The organic extracts are combined, washed with saturated aqueous sodium bicarbonate (3×30 ml), dried over sodium sulfate and filtered. Evaporation (in vacuo) of the filtrate leaves the desired ester 2 as a pale yellow oil (10.55 g): tlc, Rf =0.4 (homogeneous, UV detection) on silica gel with ethyl acetate:hexane (7:3; v:v) as eluent; ir (2% solution in chloroform) 3400 (w), 1710 (s), 1600 (s) and 1280 (s) cm-1.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:6]=1[S:7]([NH2:10])(=[O:9])=[O:8].[CH2:18]([N:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28](=[O:35])[C:27](=[C:36](SC)SC)[C:26]1=[O:41])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1(C)C=CC=CC=1>[CH2:18]([N:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([OH:35])=[C:27]([C:36]2[NH:1][C:2]3[N:3]=[CH:4][N:5]([CH2:11][C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:6]=3[S:7](=[O:9])(=[O:8])[N:10]=2)[C:26]1=[O:41])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CSC(SC)=C1C(=O)c2ccccc2N(Cc2ccccc2)C1=O
Reactant: Nc1ncn(Cc2ccccc2)c1S(N)(=O)=O
Solvent: Cc1ccccc1
Product: O=c1c(C2=NS(=O)(=O)c3c(ncn3Cc3ccccc3)N2)c(O)c2ccccc2n1Cc1ccccc1
Temperature: 25 °C
Yield: 50.3 %

Procedure:
The product of Example 312F (152 mg, 0.602 mmol) was reacted with the product of Example 309B (214 mg, 0.602 mmol) in toluene (8 mL) at 100° C. for 3 hours. The reaction was allowed to cool to 25° C. and diluted with hexanes. The resulting precipitate was collected by filtration. The residue was chromatographed on silica gel, eluting with gradient of 0-2% methanol in dichloromethane to give the title compound (155 mg, 50%). MS (ESI+) m/z 512 (M+H)+. 1H NMR (300 MHz, DMSO-d6) δ ppm 5.42 (s, 2H), 5.63 (s, 2H), 7.22-7.44 (m, 11H), 7.53-7.56 (m, 1H), 7.74-7.79 (m, 1H), 8.20-8.23 (dd, J=8.1, 1.5 Hz, 1H), 8.32 (s, 1H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:11]([O:29][CH2:30][CH2:31][O:32][C:33]4[N:38]=[CH:37][C:36]([Br:39])=[CH:35][N:34]=4)=[N:12][O:13][C:14]=3[NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:21][CH:20]=3)(=[O:18])=[O:17])=[CH:9][C:4]=2[O:3][CH2:2]1.C[OH:41]>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:11]([O:29][CH2:30][CH2:31][O:32][C:33]4[N:38]=[CH:37][C:36]([Br:39])=[CH:35][N:34]=4)=[N:12][O:13][C:14]=3[NH:15][S:16]([C:19]3[CH:20]=[CH:21][C:22]([C:25]([CH3:28])([CH3:27])[CH2:26][OH:41])=[CH:23][CH:24]=3)(=[O:18])=[O:17])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CO
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2onc(OCCOc3ncc(Br)cn3)c2-c2ccc3c(c2)OCO3)cc1
Product: CC(C)(CO)c1ccc(S(=O)(=O)Nc2onc(OCCOc3ncc(Br)cn3)c2-c2ccc3c(c2)OCO3)cc1
Reaction time: 48 h

Procedure:
Amycolata autotrophica ATCC35203 maintained on a quarter strength ATCC172 agar slope was inoculated as a loopful of spores into a 300 ml Erlenmeyer flasks each containing 50 ml of of MY inoculum medium. This was allowed to incubate for 2 days at 28° C., 200 rpm on an Infors Multitron™ Shaker with 1″ throw. Two mls of this inoculum was then transferred to each of twenty 300 ml Erlenmeyer flask containing 50 ml of MY production medium and incubated under the same conditions for a further 24 hours. At this point 5 mg of N-(4-(1,3-benzodioxol-5-yl)-3-{2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy}-5-isoxazolyl)-4-(tert-butyl)benzenesulfonamide (Preparation 20) dissolved in 0.5 ml of methanol was added to each of the flasks and the fermentation allowed to continue under the same conditions for a further 144 hours. Each flask was then extracted with 200 mls of ethyl acetate and the combined ethyl acetate solubles concentrated to dryness to give a gum solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]([N+:19]([O-])=O)=[C:17]([NH2:22])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23]([O:30][C:31]1[C:40]([N+:41]([O-])=O)=[C:39]([NH2:44])[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][N:37]=2)[N:32]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:1]([O:8][C:9]1[C:18]([NH2:19])=[C:17]([NH2:22])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23]([O:30][C:31]1[C:40]([NH2:41])=[C:39]([NH2:44])[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][N:37]=2)[N:32]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Nc1c([N+](=O)[O-])c(OCc2ccccc2)nc2cccnc12
Reactant: Nc1c([N+](=O)[O-])c(OCc2ccccc2)nc2ccccc12
Product: Nc1c(OCc2ccccc2)nc2ccccc2c1N
Product: Nc1c(OCc2ccccc2)nc2cccnc2c1N

Procedure:
In steps (6) and (7) of Reaction Scheme IV, the hydroxy group of a benzyloxy-3-nitroquinolin-4-amine or benzyloxy-3-nitro[1,5]naphthyridin-4-amine of Formula XL is protected to provide a compound of Formula XLI, which is reduced to provide a benzyloxyquinoline-3,4-diamine or benzyloxy[1,5]naphthyridine-3,4-diamine of Formula XLII. Steps (6) and (7) of Reaction Scheme IV can be carried out according to the methods described in steps (2) and (3) of Reaction Scheme I.