Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=C(Cl)C=CC=1C1N=C(CC)C(N[C@H]2[C@@H](OCC)CNC2)=NC=1CC.[Cl:28][C:29]1[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:30]=1[C:37]1[N:38]=[C:39]([CH2:57][CH3:58])[C:40]([NH:45][C@H:46]2[C@@H:50]([O:51][CH2:52][CH3:53])[CH2:49][N:48](C([O-])=O)[CH2:47]2)=[N:41][C:42]=1[CH2:43][CH3:44]>>[Cl:28][C:29]1[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:30]=1[C:37]1[N:38]=[C:39]([CH2:57][CH3:58])[C:40]([NH:45][C@H:46]2[C@@H:50]([O:51][CH2:52][CH3:53])[CH2:49][NH:48][CH2:47]2)=[N:41][C:42]=1[CH2:43][CH3:44]
Reactant: CCO[C@H]1CN(C(=O)[O-])C[C@H]1Nc1nc(CC)c(-c2ccc(OC)cc2Cl)nc1CC
Agent: CCO[C@H]1CNC[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Product: CCO[C@H]1CNC[C@H]1Nc1nc(CC)c(-c2ccc(OC)cc2Cl)nc1CC

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(cis)-4-ethoxypyrrolidin-3-yl]-3,6-diethylpyrazin-2-amine but substituting (3R,4S)-3-{[5-(2-chloro-4-methoxyphenyl)-3,6-diethylpyrazin-2-yl]amino}-4-ethoxypyrrolidine-1-carboxylate and making non-critical variations provided the title compound as an oil: 1H NMR (CDCl3) δ 1.15, 1.22–1.34, 2.45, 2.71, 2.89, 3.06, 3.22, 3.41, 3.51, 3.65, 3.85, 4.51, 5.32, 6.88, 7.02, 7.24.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:17]=[C:16](F)[N:15]=[C:14]2[C:10]=1[N:11]=[CH:12][N:13]2[CH:19]([CH3:21])[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(C)=O.[NH2:26][C@H:27]([CH2:31][CH3:32])[CH:28]([OH:30])[CH3:29]>C(Cl)Cl.CCOCC.CO>[CH2:1]([NH:8][C:9]1[N:17]=[C:16]([NH:26][C@H:27]([CH2:31][CH3:32])[CH:28]([OH:30])[CH3:29])[N:15]=[C:14]2[C:10]=1[N:11]=[CH:12][N:13]2[CH:19]([CH3:21])[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC[C@@H](N)C(C)O
Reactant: CC(C)n1cnc2c(NCc3ccccc3)nc(F)nc21
Solvent: CCOCC
Solvent: ClCCl
Solvent: CO
Product: CC[C@@H](Nc1nc(NCc2ccccc2)c2ncn(C(C)C)c2n1)C(C)O
Reaction time: 48 h

Procedure:
To a stirred solution of benzyl-(2-fluoro-9-isopropyl-9H-purin-6-yl)-amine (0.34 g, 1.19 mmol) in BunOH/DMSO (5 mL, 4:1) at RT under Ar was added Pri2NEt (2.0 mL, 11.48 mmol) followed by (2RS,3R)-3-amino-pentan-2-ol (0.16 g, 1.55 mmol). The reaction mixture was placed in a preheated oil bath at 140° C. and stirred at this temperature for 48 h, when TLC (55:40:5 CH2Cl2 Et2O/MeOH) indicated the appearance of a lower running product together with some desired product. The reaction mixture was allowed to cool to RT and the solvent was evaporated in vacuo. The residue was partitioned between CH2Cl2 (100 mL) and H2O (200 mL), the aqueous phase was extracted with more CH2Cl2 (3×50 mL), and the combined organic phase was washed with brine (50 mL), dried (MgSO4) and evaporated in vacuo. The residue was purified by gradient column chromatography on silica gel eluted with CH2Cl2/Et2O/MeOH (60:40:0→60:40:4) to afford thee title compound as a white solid (0.03 g, 7%). Mp 43-46° C. 1H-NMR (d6-DMSO, 250 MHz): δ 0.75-0.85 (m, 3H, —NHCH(CH2CH3)CH(CH3)OH), 0.95-1.03 (m, 3H, —NHCH(CH2CH3)CH(CH3)OH) 1.19-1.77 (m, 8H, —NHCH(CH2CH3)CH(CH3)OH+CH(CH3)2), 3.60+3.73 (2×m, 1H, —NHCH(CH2CH3)CH(CH3)OH), 4.44-4.78 (m, 4H, —HNCH2-Bz+—NHCH(CH2CH3)CH(CH3)OH+—CH(CH3)2), 5.57+5.87 (2×d, 1H, J=9.958+7.74 Hz, —NHCH(CH2CH3)CH(CH3)OH), 7.18-7.36 (m, 5H, Bz), 7.77 (bs, 2H, —N═CH—N—+—HNCH2-Bz). FAB-MS m/z (relative intensity): 369 ([M+H]+, 100), 323 (96), 233 (30). Accurate Mass (M+H): Actual: 369.2403, Measured: 369:2393 Microanalysis (Expected:Measured) C20H28N6O.0.5H2O: C, 63.64:64.17; H, 7.74:7.56; N, 22.26:21.38.
Reaction SMILES: [C:1]([C:7]1[CH:12]=[CH:11][N:10]([C@@H:13]2[O:35][C@H:34]([CH2:36][O:37]C(=O)C3C=CC=CC=3)[C@@H:24]([O:25]C(=O)C3C=CC=CC=3)[C@H:14]2[O:15]C(=O)C2C=CC=CC=2)[C:9](=[O:46])[N:8]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH3:6].[NH3:47]>>[NH2:47][C:2]([CH2:3][CH2:4][CH2:5][CH3:6])=[CH:1][C:7]1[CH:12]=[CH:11][N:10]([C@@H:13]2[O:35][C@H:34]([CH2:36][OH:37])[C@@H:24]([OH:25])[C@H:14]2[OH:15])[C:9](=[O:46])[N:8]=1
Reactant: N
Reactant: CCCCC#Cc1ccn([C@@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@H]2OC(=O)c2ccccc2)c(=O)n1
Product: CCCCC(N)=Cc1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)n1

Procedure:
A solution of 14a (1.2 g, 1.9 mmol) in methanolic ammonia (saturated at −20° C.) was stirred in a pressure bottle for 18 hr. Evaporation of the solvents and flash chromatography of the residue using ethyl acetate/methanol (4:1) gave 17a as a light yellow solid, 0.47 g (77%). 1H-NMR (DMSO-d6): δ10.2 and 7.7 (2 bs, 2H, NH2); 7.83 (d, 1H, H-6, J6,5=6.9 Hz); 5.78 (s, 1H, H-1′); 4.72 (s, 1H, vinylic); 2.17, 1.50, 1.30 and 0.90 (4 m, 9H, n-butyl).
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8](B3OC(C)(C)C(C)(C)O3)[CH:9]=2)[N:4]=1.I[C:23]1[C:31]2[S:30][N:29]=[C:28]([NH2:32])[C:27]=2[CH:26]=[CH:25][C:24]=1[CH3:33].C(=O)([O-])[O-].[Na+].[Na+].CN(C=O)C>O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:32][C:28]1[C:27]2[CH:26]=[CH:25][C:24]([CH3:33])=[C:23]([C:8]3[CH:9]=[C:10]4[C:5](=[CH:6][CH:7]=3)[N:4]=[C:3]([NH:2][CH3:1])[N:12]=[CH:11]4)[C:31]=2[S:30][N:29]=1
Reactant: Cc1ccc2c(N)nsc2c1I
Reactant: CNc1ncc2cc(B3OC(C)(C)C(C)(C)O3)ccc2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CNc1ncc2cc(-c3c(C)ccc4c(N)nsc34)ccc2n1
Temperature: 150 °C

Procedure:
N-Methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-amine (0.42 g, 1.5 mmol), 7-iodo-6-methylbenzo[d]isothiazol-3-amine (0.39 g, 1.3 mmol), dichlorobis(triphenyl-phosphine)palladium (II) (0.047 g, 0.067 mmol) and sodium carbonate (0.14 g, 1.3 mmol) were all placed in a clear microwave vial along with 5 ml of 9:1 DMF:water. The vial was capped and heated in a Personal Chemistry SmithSynthesizer to 150° C. for 10 minutes. The reaction was diluted with water and extracted with EtAOc. The organic layer was washed (2×) with an aqueous saturated solution of sodium bicarbonate, then with water and then brine. The organic layer was then dried with sodium sulfate and purified by column chromatography on silica gel using a gradient of 50 to 100% EtOAc in hexanes. The clean fractions were triturated with warm ether and the solid collected by suction filtration and dried to give 6-(3-amino-6-methylbenzo[d]isothiazol-7-yl)-N-methylquinazolin-2-amine as a tan solid. MS (M+H)+ 322.
Reaction SMILES: [C:1]([C:4]1[C:33]2=[N:34][C:30]3=[CH:31][N:32]2[C:7]([N:8]2[CH2:39][CH2:38][C:11]([CH3:40])([O:12][CH2:13][CH2:14][CH2:15][CH2:16][C@H:17]([CH3:37])[O:18][C:19]4[CH:20]=[CH:21][C:22]([F:36])=[CH:23][C:24]=4[C:25]4[CH:35]=[C:29]3[CH:28]=[CH:27][CH:26]=4)[CH2:10][CH2:9]2)=[C:6]([C@H:41]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])[C:42]([O:44]C)=[O:43])[C:5]=1[CH3:51])(=[O:3])[CH3:2].C(O[C@@H](C1C(C)=CC2=NC3=C(Cl)N2C=1N1CCC(C)(OCCCC[C@H](C)OC2C=CC(C)=CC=2C2C=C3C=CC=2)CC1)C(O)=O)(C)(C)C>>[C:1]([C:4]1[C:33]2=[N:34][C:30]3=[CH:31][N:32]2[C:7]([N:8]2[CH2:9][CH2:10][C:11]([CH3:40])([O:12][CH2:13][CH2:14][CH2:15][CH2:16][C@H:17]([CH3:37])[O:18][C:19]4[CH:20]=[CH:21][C:22]([F:36])=[CH:23][C:24]=4[C:25]4[CH:35]=[C:29]3[CH:28]=[CH:27][CH:26]=4)[CH2:38][CH2:39]2)=[C:6]([C@H:41]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])[C:42]([OH:44])=[O:43])[C:5]=1[CH3:51])(=[O:3])[CH3:2]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)c(C(C)=O)c2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1ccc(F)cc1-c1cccc-3c1
Agent: Cc1ccc2c(c1)-c1cccc(c1)-c1nc3cc(C)c([C@H](OC(C)(C)C)C(=O)O)c(n3c1Cl)N1CCC(C)(CC1)OCCCC[C@H](C)O2
Product: CC(=O)c1c(C)c([C@H](OC(C)(C)C)C(=O)O)c2n3cc(nc13)-c1cccc(c1)-c1cc(F)ccc1O[C@@H](C)CCCCOC1(C)CCN2CC1
Yield: 4.3 %

Procedure:
Prepared in 4.3% yield from methyl(2S)-2-[(22S)-5-acetyl-17-fluoro-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]-2-(tert-butoxy)acetate following the procedure for (2S)-2-(tert-butoxy)-2-[(22S)-8-chloro-4,17,22,28-tetramethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetic acid. 1H NMR (500 MHz, DMSO-d6) δ 8.16 (s, 1H), 8.09 (d, J=7.7 Hz, 1H), 8.03 (s, 1H), 7.53 (t, J=7.5 Hz, 1H), 7.36 (d, J=7.7 Hz, 1H), 7.23-7.13 (m, 3H), 5.85 (br. s., 1H), 4.61 (br. s., 1H), 3.87-3.79 (m, 1H), 3.63-3.55 (m, 1H), 3.45 (br. s., 3H), 3.33 (br. s., 1H), 2.76 (s, 3H), 2.67 (d, J=8.1 Hz, 1H), 2.28 (s, 3H), 1.89-1.61 (m, 9H), 1.51 (br. s., 1H), 1.19 (s, 3H), 1.15 (s, 9H), 1.06 (d, J=5.9 Hz, 3H); LCMS (ESI, M+1): 686.4.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][N:4]=1)[NH2:2].[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=1[CH2:19][C:20](=O)[CH2:21][C:22](OC)=[O:23]>>[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=1[CH2:19][C:20]1[CH:21]=[C:22]([OH:23])[N:1]([C:3]2[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][N:4]=2)[N:2]=1
Reactant: N#Cc1ccnc(NN)c1
Reactant: COC(=O)CC(=O)Cc1c(F)cccc1F
Product: N#Cc1ccnc(-n2nc(Cc3c(F)cccc3F)cc2O)c1

Procedure:
The title compound was prepared from 2-hydrazinylpyridine-4-carbonitrile (PREPARATION 2) and methyl 4-(2,6-difluorophenyl)-3-oxobutanoate according to the procedure for the preparation of Example 158, part A.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=2)=[C:4]([OH:22])[N:3]=1.C1(NP(Cl)(=O)OC2C=CC=CC=2)C=CC=CC=1.CN1CCOCC1.Cl.[NH2:48][C@H:49]([C:57]([O:59][CH2:60][CH3:61])=[O:58])[CH2:50][CH2:51][C:52]([O:54][CH2:55][CH3:56])=[O:53]>CN1CCCC1=O>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:17]([NH:48][C@H:49]([C:57]([O:59][CH2:60][CH3:61])=[O:58])[CH2:50][CH2:51][C:52]([O:54][CH2:55][CH3:56])=[O:53])=[O:19])=[CH:20][CH:21]=2)=[C:4]([OH:22])[N:3]=1
Reactant: CCOC(=O)CC[C@H](N)C(=O)OCC
Reactant: Nc1nc(N)c(CCCCc2ccc(C(=O)O)cc2)c(O)n1
Agent: Cl
Agent: O=P(Cl)(Nc1ccccc1)Oc1ccccc1
Solvent: CN1CCCC1=O
Solvent: CN1CCOCC1
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(CCCCc2c(N)nc(N)nc2O)cc1)C(=O)OCC
Reaction time: 1 h

Procedure:
A mixture of 0.47 g (1.0 eq) of 4-[4-(2,4-diamino-6-hydroxypyrimidin-5-yl)butyl]benzoic acid, 0.62 g (1.5 eq) of phenyl N-phenylphosphoramidochloridate, 0.79 g (5.0 eq) of N-methylmorpholine, and 50 mL of anhydrous N-methylpyrrolidone is stirred under nitrogen at ambient temperatures for one hour. There is then added 0.75 g (2.0 eq) of diethyl L-glutamate hydrochloride and stirring is continued under nitrogen for 24 hours. The solvent is removed by vacuum distillation and chloroform was added to the residue. The chloroform solution is washed with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue is chromatographed with 1:9 methanol:chloroform to yield diethyl N-(4-[4-(2,4-diamino-6-hydroxypyrimidin-5-yl)butyl]benzoyl)-L-glutamate, m.p. 75°-76° C.; IR (KBr) vmax 3320, 2920, 2915, 1845, 1720, 1580, 1529, 1427, 1368, 1326, 1192, 1093, 1021, 849 and 750 cm-1 ; 1H NMR (CDCl3) delta 11.58 (bs, 1 H (3)--NH), 7.68 (d, J=7.9 Hz, 2H, Ar), 7.33 (d, J=7.9 Hz, 1H, NH), 7.17 (d, J=7.9 Hz, 2H, Ar), 5.54 (bs, 2H (2)--NH2), 4.76-4.82 (m, 1H, CH), 4.71 (bs, 2H, (6)--NH2), B 4.23 (q, J=7.11 Hz, 2H, CO2CH2), 4.12 (q, J=6.5 Hz, 2H, CO2CH2), 2.15-2.68 (m, 8H, 2° aliphatic) 1.57-1.66 (m, 2H, 2° aliphatic), 1.35-1.45 (m, 2H, 2° aliphatic), 1.30 (t, J=7.1 Hz, 3H, CH3), 1.22 (t, J=7.1 Hz, 3H, CH3); HRMS calcd for C24H33N5O6 (M+): 487.2430; found: 487.2415; other ions at m/e 348, 313, 285, 195, 167, 139, 97, and 84.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][NH2+:18]3)=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:10])(=[O:9])[N:8]=1.[CH3:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[N:30]=[CH:29][CH:28]=[C:27]2[C:34](O)=[O:35]>>[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][N:18]3[C:34]([C:27]3[C:26]4[C:31](=[CH:32][CH:33]=[C:24]([CH3:23])[CH:25]=4)[N:30]=[CH:29][CH:28]=3)=[O:35])=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:9])(=[O:10])[N:8]=1
Reactant: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3CCCC[NH2+]3)c21
Reactant: Cc1ccc2nccc(C(=O)O)c2c1
Agent: Cl
Product: Cc1ccc2nccc(C(=O)N3CCCC[C@@H]3COc3cccc4c3C(N)=NS(=O)(=O)N4)c2c1

Procedure:
Prepared as in Example 15 from (R)-2-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidinium hydrochloride (Example 15a) and 6-methylquinoline-4-carboxylic acid. 1H NMR (400 MHz, DMSO-d6) δ 1.34-1.53 (m, 2H), 1.59-1.86 (m, 4H), 2.01 (s, 3H), 3.01 (m, 1H), 3.20 (m, 1H), 4.19 (dd, 1H, J=10.1, 3.2 Hz), 4.95 (t, 1H, J=10.6 Hz), 5.46 (m, 1H), 6.67 (d, 1H, J=8.1 Hz), 7.01 (d, 1H, J=8.3 Hz), 7.34 (s, 1H), 7.48-7.56 (m, 2H), 7.60-7.68 (m, 1H), 7.92 (d, 1H, J=8.7 Hz), 7.99 (br s, 1H), 8.27 (br s, 1H), 8.87 (d, 1H, J=4.4 Hz), 10.94 (s, 1H). MS 480 (MH+).
Reaction SMILES: [CH:1]1([NH:11][C:12]([NH2:14])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.C(O)(=[O:17])C>O>[O:17]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]([NH:11][C:12]([NH2:14])=[O:13])[CH2:2][CH2:3]1
Reactant: CC(=O)O
Reactant: NC(=O)NC1CCCc2ccccc21
Solvent: O
Product: NC(=O)NC1CCC(=O)c2ccccc21

Procedure:
A solution of 0.5 g of 1,2,3,4-tetrahydro-1-naphthylurea in 50 ml of 50% aqueous acetic acid is cooled to below 5° C and 6.0 g of ceric ammonium nitrate added. After 5 minutes the mixture is diluted with water and extracted with 3 × 5 ml of ethyl acetate. The extracts are combined and evaporated to dryness to afford the crude title product.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Cl)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([O:8][CH2:15][C:14]2[CH:17]=[CH:18][C:11]([O:10][CH3:9])=[CH:12][CH:13]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Oc1cccnc1Cl
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(COc2cccnc2Cl)cc1
Temperature: 60 °C
Reaction time: 17 h
Yield: 87 %

Procedure:
2-Chloro-3-pyridinol (1.3 g), 1.88 g of p-methoxybenzyl chloride, and 1.4 g of potassium carbonate were added to 10 ml of dimethylformamide, followed by stirring at 60° C. for 17 hours. The reaction mixture was diluted with ethyl acetate and washed successively with water and a saturated sodium chloride aqueous solution. After drying, the solvent was removed by evaporation, and the residue was subjected to silica gel column chromatography using a 1:4 (by volume) mixture of ethyl acetate and hexane as a developing solution. The fraction containing the desired compound was concentrated to afford 2.18 g of the title compound.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:28]=[CH:27][CH:26]=[CH:25][C:8]=1[CH:9]=[C:10]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH2:14][CH2:13][C:12]2[CH:21]=[CH:22][CH:23]=[CH:24][C:11]1=2.[B:29](OC(C)C)([O:34]C(C)C)[O:30]C(C)C.Cl>C1COCC1>[CH:21]1[C:12]2[CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:10](=[CH:9][C:8]3[CH:25]=[CH:26][CH:27]=[CH:28][C:7]=3[B:29]([OH:34])[OH:30])[C:11]=2[CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Brc1ccccc1C=C1c2ccccc2CCc2ccccc21
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccccc1C=C1c2ccccc2CCc2ccccc21
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Add n-BuLi (1.6M in hexanes, 12.98 Ml, 20.76 mmol) portionwise (exothermic) to a solution of 5-(2-bromo-benzylidene)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (5.00 g, 13.84 mmol) in dry THF (50 Ml) at −78° C. under N2. Let stir at −78° C. for 30 min, then add triisopropyl borate (5.21 g, 27.68 mmol) and warm up to room temperature overnight. Add 50 Ml 1.00N HCl and stir for 15 min. Extract into ethyl acetate, dry (MgSO4) and concentrate organics to a brown foam. Recrystallize from boiling hexanes, then chromatograph on silica gel (40 g), eluting with 20% to 50% ethyl acetate/hexanes to afford the title compound as a white foam, mp 134.1° C. MS (ES) 325 (M−H); HPLC shows 82% purity.
Reaction SMILES: [N+:1]([CH:4]=[CH:5][C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)([O-:3])=[O:2].[CH3:11][N:12]([CH3:16])[C:13](=[S:15])[S-:14].C[NH2+]C>C(=S)=S>[CH3:11][N:12]([CH3:16])[C:13](=[S:14])[S:15][CH:5]([CH2:4][N+:1]([O-:3])=[O:2])[C:6]1[S:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=[N+]([O-])C=Cc1cccs1
Reactant: CN(C)C(=S)[S-]
Agent: C[NH2+]C
Solvent: S=C=S
Product: CN(C)C(=S)SC(C[N+](=O)[O-])c1cccs1

Procedure:
As in Example 17, reaction of 2-(2-nitrovinyl)thiophene with dimethylammonium dimethyldithiocarbamate in the presence of carbon disulfide gave α-(nitromethyl)-2-thenyl dimethyldithiocarbamate melting at 88°-90° C. when recrystallized without heating from acetone-ethanol solution.
Reaction SMILES: [Cl:1][C:2]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:3]=1[NH:4][C:5](=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:27])=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:3]=1[NH:4][C:5](=[S:27])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Cc1cccc(NC(=O)c2ccccc2)c1Cl
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: Cc1cccc(NC(=S)c2ccccc2)c1Cl

Procedure:
98 g (0.4 mol) of the compound from Example V and 162 g (0.4 mol) of Lawesson's reagent were boiled in 1 l of toluene overnight, and the mixture was concentrated and purified on SiO2 (cyclohexane/ethyl acetate=8:2) Yield: 93 g (80% of theory) as a yellow oil.
Reaction SMILES: CC1(C)COB(B2OCC(C)(C)CO2)OC1.C([O-])(=O)C.[K+].Br[C:23]1[CH:28]=[CH:27][C:26]([C:29]2([OH:33])[CH2:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1.Br[C:35]1[C:36]([F:47])=[C:37]2[C:41](=[CH:42][C:43]=1[F:44])[NH:40][CH:39]=[C:38]2[CH:45]=[O:46].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CCO.C1(C)C=CC=CC=1>[F:47][C:36]1[C:35]([C:23]2[CH:28]=[CH:27][C:26]([C:29]3([OH:33])[CH2:32][CH2:31][CH2:30]3)=[CH:25][CH:24]=2)=[C:43]([F:44])[CH:42]=[C:41]2[C:37]=1[C:38]([CH:45]=[O:46])=[CH:39][NH:40]2
Reactant: O=Cc1c[nH]c2cc(F)c(Br)c(F)c12
Reactant: OC1(c2ccc(Br)cc2)CCC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: O=Cc1c[nH]c2cc(F)c(-c3ccc(C4(O)CCC4)cc3)c(F)c12
Temperature: 110 °C
Yield: 66.5 %

Procedure:
A mixture of 5,5,5′,5′-tetramethyl-2,2′-bi(1,3,2-dioxaborinane) (188.0 mg, 0.55 mmol), oven dried potassium acetate (230.0 mg, 2.34 mmol), and 1-(4-bromophenyl)cyclobutanol (114.0 mg, 0.50 mmol) in 1,4-dioxane (2 mL) was degassed with N2 for 15 min, then treated with [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (20.0 mg, 0.027 mmol). The reaction mixture was subjected to microwave irradiation at 110° C. for 1 hour. The cooled reaction mixture was filtered through celite, rinsed with EtOAc and concentrated to dryness. To the resulting dark solid ((45.0 mg, 0.17 mmol) was added 5-bromo-4,6-difluoro-1H-indole-3-carbaldehyde (45.0 mg, 0.17 mmol), 2 N aqueous potassium carbonate (0.20 mL, 0.40 mmol), toluene (1.5 mL) and EtOH (0.5 mL). The reaction mixture was degassed with N2 for 10 minutes, treated with [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (14.0 mg, 0.019 mmol), and heated in a sealed pressure tube at 110° C. for 2 hours. The reaction mixture was cooled to room temperature and purified by flash chromatography (0-67% EtOAc/heptanes) to give the title compound (37 mg, 65%) as a white solid. MS (ES+) 328.0 (M+H)+. 1H NMR (500 MHz, CD3OD) δ 10.04 (d, J=2.68 Hz, 1 H), 8.15 (s, 1 H), 7.64 (d, J=8.05 Hz, 2 H), 7.48 (d, J=8.05 Hz, 2 H), 7.21 (d, J=9.51 Hz, 1 H), 2.57-2.66 (m, 2 H), 2.39-2.46 (m, 2 H), 2.03-2.12 (m, 1 H), 1.73-1.83 (m, 1 H).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[N:6][C:7]([CH2:11][CH2:12][CH:13]=O)=[CH:8][CH:9]=2)[CH2:4][O:3]1.[CH3:15][NH:16][CH2:17][CH:18]([OH:21])[CH2:19][OH:20]>>[OH:21][CH:18]([CH2:19][OH:20])[CH2:17][N:16]([CH3:15])[CH2:13][CH2:12][CH2:11][C:7]1[N:6]=[C:5]2[CH2:4][O:3][C:2](=[O:1])[C:10]2=[CH:9][CH:8]=1
Reactant: O=CCCc1ccc2c(n1)COC2=O
Reactant: CNCC(O)CO
Product: CN(CCCc1ccc2c(n1)COC2=O)CC(O)CO
Yield: 52.8 %

Procedure:
In a process similar to that described in Preparation 8, 3-(5-Oxo-5,7-dihydro-furo[3,4-b]pyridin-2-yl)-propionaldehyde (139 mg, 0.73 mmol) and 3-methylamino-1,2-propanediol (77 mg, 0.73 mmol) are reacted to provide the title compound as an oil (108 mg, 52%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[N:25]1([CH2:30][CH2:31][CH2:32][NH2:33])[CH2:29][CH2:28][CH2:27][CH2:26]1.C(O)(C(F)(F)F)=O>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:33][CH2:32][CH2:31][CH2:30][N:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)=[O:21])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2]
Reactant: NCCCN1CCCC1
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)NCCCN3CCCC3)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 74 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 3-(pyrrolidin-1-yl)propan-1-amine as a TFA salt. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.80-1.96 (m, 4 H) 1.97-2.08 (m, 2 H) 2.44 (s, 3 H) 2.91-3.09 (m, 2 H) 3.21 (dt, J=10.36, 5.43 Hz, 2 H) 3.38 (q, J=6.40 Hz, 2 H) 3.49-3.64 (m, 2 H) 7.67 (d, J=7.58 Hz, 1 H) 7.74 (s, 2 H) 8.03-8.33 (m, 1 H) 8.43 (br. s., 2 H) 8.85 (br. s., 1 H) 8.88-8.98 (m, 1 H) 9.50 (br. s., 1 H) 12.61-13.62 (m, 1 H). MS m/z [M+H]+ 431.2
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+].[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][NH:23][C:22](=[O:26])[CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(#N)C>[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][N:23]([CH2:2][CH:3]2[CH2:5][CH2:4]2)[C:22](=[O:26])[CH:21]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: BrCC1CC1
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=c1cc(OCc2ccccc2)ccn1CC1CC1
Yield: 99.7 %

Procedure:
Bromomethyl-cyclopropane (3.68 g, 27.33 mmol) and potassium carbonate (10.3 g, 74.52 mmol) were added to a solution of 4-benzyloxy-1H-pyridin-2-one (5.0 g, 24.84 mmol) in acetonitrile (200 ml) and the mixture was heated at reflux temperature for 16 hours. The reaction mixture was filtered through diatomaceous earth and concentrated in vacuo. The crude residue was then triturated with diethylether to yield pure D1 (6.32 g, 98%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.C([Li])(C)(C)C.[F:15][C:16]1[CH:17]=[CH:18][C:19]([O:29][CH3:30])=[C:20]([C:22]([CH3:28])([CH3:27])[CH2:23][C:24](=[O:26])[CH3:25])[CH:21]=1>C1COCC1>[F:15][C:16]1[CH:17]=[CH:18][C:19]([O:29][CH3:30])=[C:20]([C:22]([CH3:27])([CH3:28])[CH2:23][C:24]([CH2:1][C:2]2[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=2)([OH:26])[CH3:25])[CH:21]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC(C)=O
Reactant: Cc1cc(C)nc(C)c1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COc1ccc(F)cc1C(C)(C)CC(C)(O)Cc1cc(C)cc(C)n1
Temperature: -70 °C
Reaction time: 0.03 h
Yield: 56.1 %

Procedure:
To a solution of 2,4,6-trimethylpyridine (0.14 g) in THF (1 mL) stirred under argon and cooled to −70° C., tert-butyl lithium (1.7M in pentane, 0.75 mL) was added dropwise over 2 minutes. After stirring for an additional 2 minutes, 4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-one (Example 17) (0.22 g) in THF (0.8 mL) was added all at once. After 5 minutes, the reaction was quenched with EtOH (0.2 mL) and allowed to warm to room temperature. The mixture was diluted with EtOAc, washed with water, dried, filtered, and evaporated. Chromatography of the residue over silica gel (eluent: EtOAc-methylene chloride (2:98 to 8:92 gradient)) gave the product as an oil (0.19 g).
Reaction SMILES: [ClH:1].[CH2:2]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]=2[CH2:5][CH2:4][NH:3]1.C1(NN)C=CC=CC=1>>[ClH:1].[Cl:1][C:10]1[CH:11]=[CH:12][C:13]2[C:14]3[CH2:2][NH:3][CH2:4][CH2:5][C:6]=3[N:7]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:8]=2[CH:9]=1
Reactant: CCOC(=O)Cn1c2c(c3ccccc31)CNCC2
Agent: Cl
Solvent: NNc1ccccc1
Product: CCOC(=O)Cn1c2c(c3ccc(Cl)cc31)CNCC2

Procedure:
The title compound is prepared using a procedure analogous to Intermediate 1, substituting 3-chlorophenylhydrazine for phenylhydrazine in Step 1a).