Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([CH2:12][N:13]([CH3:15])[CH3:14])[CH2:8][NH:9]2)=[CH:4][CH:3]=1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>N1C=CC=CC=1.C1COCC1>[C:16]([NH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([CH2:12][N:13]([CH3:15])[CH3:14])[CH2:8][NH:9]2)=[CH:4][CH:3]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: CN(C)CC1CNc2cc(N)ccc2C1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc2c(c1)NCC(CN(C)C)C2
Reaction time: 0.5 h
Yield: 76.1 %

Procedure:
To a solution of 7-amino-3-(N,N-dimethylamino)methyl-1,2,3,4-tetrahydroquinoline (300 mg) in pyridine (3 ml) was added a solution of acetic anhydride (150 mg) in THF (1 ml) and stirring was continued for 30 minutes. The reaction mixture was purified by alumina column chromatography (eluent; ethyl acetate to ethyl acetate/methanol=20:1) and the resulting crystals were washed with IPE to obtain the entitled compound (275 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][CH:16]=[CH:15][C:5]=1[O:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[C:10]#[N:11])([O-])=O.O.O.Cl[Sn]Cl>CCO>[NH2:1][C:4]1[CH:18]=[CH:17][CH:16]=[CH:15][C:5]=1[O:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[C:10]#[N:11]
Reactant: N#Cc1cccc(Oc2ccccc2[N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: N#Cc1cccc(Oc2ccccc2N)c1
Yield: 98.9 %

Procedure:
A solution of 3-(2-nitrophenoxy)benzonitrile (1.21 g, 5 mmol, 1.0 equiv) in 30 mL of EtOH was treated with SnCl2.2H2O (3.38 g, 3 equiv) at reflux for 4 h. The volatile was evaporated and the residue was redissolved in EtOAc, washed with saturated aqueous NaHCO3 and 1N NaOH. The organic layer was dried over MgSO4, filtered and evaporated to give 3-(2-aminophenoxy)benzonitrile (1.04 g, 99%). MS found for C13H11N2O (M+H)+: 211.
Reaction SMILES: C([O:8][C:9]1[CH:65]=[CH:64][C:12]([C:13]([O:15][C@H:16]2[CH2:25][C:24]3[C:19](=[CH:20][C:21]([O:34]CC4C=CC=CC=4)=[CH:22][C:23]=3[O:26]CC3C=CC=CC=3)[O:18][C@@H:17]2[C:42]2[CH:47]=[CH:46][C:45]([O:48]CC3C=CC=CC=3)=[C:44]([O:56]CC3C=CC=CC=3)[CH:43]=2)=[O:14])=[CH:11][CH:10]=1)C1C=CC=CC=1.C1COCC1.CO>[OH-].[OH-].[Pd+2].CO.C(Cl)Cl>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([O:15][C@H:16]2[CH2:25][C:24]3[C:19](=[CH:20][C:21]([OH:34])=[CH:22][C:23]=3[OH:26])[O:18][C@@H:17]2[C:42]2[CH:47]=[CH:46][C:45]([OH:48])=[C:44]([OH:56])[CH:43]=2)=[O:14])=[CH:64][CH:65]=1
Reactant: O=C(O[C@H]1Cc2c(OCc3ccccc3)cc(OCc3ccccc3)cc2O[C@@H]1c1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)c1ccc(OCc2ccccc2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O[C@H]1Cc2c(O)cc(O)cc2O[C@@H]1c1ccc(O)c(O)c1)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 86.9 %

Procedure:
Under an H2 atmosphere, Pd(OH)2/C (20%, 100 mg) was added to a solution of 102 (200 mg, 0.23 mmol) in a solvent mixture of THF/MeOH (1:1 v/v, 20 mL). The resulting reaction mixture was stirred at r.t. under H2 for 6 h, TLC showed that the reaction was completed. The reaction mixture was filtered to remove the catalyst. The filtrate was evaporated, and the residue was rapidly purified by flash chromatograph on silica gel (10% MeOH/CH2Cl2, then 20% MeOH/CH2Cl2) to afford 11 (82 mg, 87% yield): mp. 220-222° C. (decomposed); [α]D=+87.2 (c=2.0, EtOH); 1H NMR (acetone-d6, 400 MHz): δ 7.98 (d, J=8.8 Hz, 2H), 7.13 (s, 1H), 7.04 (d, J=8.8 Hz, 2H), 6.99-6.96 (m, 2H), 6.27 (d, J=2.2 Hz, 1H), 6.19 (d, J=2.2 Hz, 1H), 5.62 (dd, J=11.8, 6.3 Hz, 1H), 5.34 (d, J=6.3 Hz), 3.15 (A of ABq, J=16.5, 5.2 Hz, 1H), 3.00 (B of ABq, J=16.5, 6.4 Hz, 1H); 13C NMR (acetone-d6, 400 MHz): δ 163.3, 160.0, 155.2, 154.5, 153.6, 143.1, 129.9, 128.7, 119.6, 116.6, 113.4, 113.3, 111.8, 111.7, 96.7, 93.8, 93.0, 76.2, 67.9, 21.9; HRMS (ESI) calcd for C22H18O8Na (M+Na) 433.0899, found 433.0909.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH:10]([CH:21]([CH2:32][CH2:33][CH2:34]/[CH:35]=[CH:36]\[CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:22][CH2:23][CH2:24]/[CH:25]=[CH:26]\[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:11][CH2:12][CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:8].[CH3:42][NH:43][CH3:44]>C(O)C>[CH3:42][N:43]([CH3:44])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH:10]([CH:21]([CH2:32][CH2:33][CH2:34]/[CH:35]=[CH:36]\[CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:22][CH2:23][CH2:24]/[CH:25]=[CH:26]\[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:11][CH2:12][CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:8]
Reactant: CNC
Reactant: CCCCC/C=C\CCCC(CCC/C=C\CCCCC)C(CCC/C=C\CCCCC)OC(=O)CCCCCBr
Solvent: CCO
Product: CCCCC/C=C\CCCC(CCC/C=C\CCCCC)C(CCC/C=C\CCCCC)OC(=O)CCCCCN(C)C
Temperature: 70 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
To (6Z,16Z)-12-((Z)-dec-4-enyl)docosa-6,16-dien-11-yl 6-bromohexanoate 10 (3.1 g, 4.9 mmol) in a teflon sealed pressure vessel was added 5.6 M dimethylamine in ethanol (20 mL) and the reaction was heated to 70° C. and stirred overnight. Once complete, the reaction was concentrated in vacuo to dryness. The residue was dissolved in ethyl acetate (100 mL) and washed with sodium bicarbonate solution (2×50 mL). The ethyl acetate layer was dried on magnesium sulfate, filtered, and concentrated in vacuo to dryness. The residue was purified by column chromatography (100% EtOAc) to afford (6Z,16Z)-12-((Z)-dec-4-enyl)docosa-6,16-dien-11-yl 6-(dimethylamino)hexanoate 11 as a pale yellow oil (2.0 g, 69%), 1H NMR (400 MHz, CDCl3) δ 5.36 (m, 6H), 4.93 (m, 1H), 2.27 (m, 10H), 2.00 (m, 12H), 1.63 (m, 6H), 1.51 (m, 6H), 1.28 (m, 25H), 0.90 (m, 9H). Rf 0.3 (10% MeOH—CH2Cl2).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C@@H:5]1[N:10]2[C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([NH2:21])[C:12]=3[N:22]=[C:9]2[CH2:8][O:7][CH2:6]1.C(N(CC)CC)C.[C:30](Cl)(=[O:34])[CH:31]([CH3:33])[CH3:32]>C(Cl)Cl>[NH2:21][C:13]1[C:12]2[N:22]=[C:9]3[CH2:8][O:7][CH2:6][C@H:5]([CH2:4][CH2:3][CH2:2][NH:1][C:30](=[O:34])[CH:31]([CH3:33])[CH3:32])[N:10]3[C:11]=2[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1
Reactant: CC(C)C(=O)Cl
Reactant: NCCC[C@H]1COCc2nc3c(N)nc4ccccc4c3n21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C(=O)NCCC[C@H]1COCc2nc3c(N)nc4ccccc4c3n21
Temperature: 0 °C
Reaction time: 8 h
Yield: 34 %

Procedure:
(11S)-11-(3-Aminopropyl)-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-6-amine (190 mg, 0.640 mmol) was dissolved in 8 mL of CH2Cl2 and the reaction mixture was cooled to 0° C. under N2. Triethylamine (356 μL, 2.56 mmol) was added followed by iso-butyryl chloride (67 μL, 0.643 mmol). After stirring overnight, the reaction mixture was diluted with 20 mL of CH2Cl2 and was washed successively with saturated NaHCO3 solution, H2O and brine. The organic portion was dried over Na2SO4, filtered and concentrated under reduced pressure. Chromatography (SiO2, 10% methanol/CHCl3) gave a white solid. Crystallization from ethyl acetate gave N-{3-[(11S)-6-amino-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-11-yl]propyl}-2-methylpropanamide (80 mg) as a white solid, mp 207-208° C.
Reaction SMILES: C([Li])CCC.[CH2:6]([OH:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:14]([C@@H:21]([CH2:33][CH:34]=[CH2:35])[C:22](N1[C@@H](C(C)C)COC1=O)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Cl-].[NH4+]>O1CCCC1.CCCCCC>[CH2:14]([C@H:21]([CH2:33][CH:34]=[CH2:35])[C:22]([O:13][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C=CC[C@H](Cc1ccccc1)C(=O)N1C(=O)OC[C@@H]1C(C)C
Reactant: OCc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=CC[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Reaction time: 0.17 h
Yield: 93.8 %

Procedure:
5.63 ml (9.01 mmoles) of butyllithium (as a 1.6M hexane solution) were added, whilst ice-cooling and under an atmosphere of nitrogen, to a solution of 1.24 ml (12.0 mmoles) of benzyl alcohol in 20 ml of anhydrous tetrahydrofuran. The mixture was stirred for 10 minutes, and then a solution of 1.81 g (6.01 mmoles) of 3-[2(R)-benzyl-4-pentenoyl]-4(S)-isopropyl-2-oxazolidinone (prepared by a procedure similar to that described in Preparation 17) in 10 ml of anhydrous tetrahydrofuran was added dropwise thereto. The mixture was then stirred for 30 minutes, after which a saturated aqueous solution of ammonium chloride was added to the reaction mixture, which was then extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, the solvent was removed by distillation under reduced pressure, and the residue was purified by medium pressure silica gel column chromatography (using a 10:1 by volume mixture of hexane and ethyl acetate as eluent), to give 1.58 g (yield 94%) of the title compound as a colorless oily substance.
Reaction SMILES: C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.[NH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][C:21]=1[C@H:22]1[CH2:27][C@@H:26]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[C@@H:25]([O:36][CH2:37][CH2:38][S:39]([CH3:42])(=[O:41])=[O:40])[C@@H:24]([CH3:43])[CH2:23]1.[F:44][C:45]1[CH:50]=[CH:49][CH:48]=[C:47]([F:51])[C:46]=1[C:52]1[N:57]=[C:56]([C:58]([OH:60])=[O:59])[CH:55]=[CH:54][C:53]=1[F:61]>CN(C=O)C.O>[F:44][C:45]1[CH:50]=[CH:49][CH:48]=[C:47]([F:51])[C:46]=1[C:52]1[N:57]=[C:56]([C:58]([NH:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][C:21]=2[C@@H:22]2[CH2:27][C@H:26]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[C@H:25]([O:36][CH2:37][CH2:38][S:39]([CH3:42])(=[O:41])=[O:40])[C@H:24]([CH3:43])[CH2:23]2)=[O:59])[CH:55]=[CH:54][C:53]=1[F:61].[F:51][C:47]1[CH:48]=[CH:49][CH:50]=[C:45]([F:44])[C:46]=1[C:52]1[N:57]=[C:56]([C:58]([NH:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][C:21]=2[C@H:22]2[CH2:27][C@@H:26]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[C@@H:25]([O:36][CH2:37][CH2:38][S:39]([CH3:42])(=[O:41])=[O:40])[C@@H:24]([CH3:43])[CH2:23]2)=[O:60])[CH:55]=[CH:54][C:53]=1[F:61]
Reactant: O=C(O)c1ccc(F)c(-c2c(F)cccc2F)n1
Reactant: C[C@H]1C[C@@H](c2ccncc2N)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1OCCS(C)(=O)=O
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H]1C[C@H](c2ccncc2NC(=O)c2ccc(F)c(-c3c(F)cccc3F)n2)C[C@H](NC(=O)OC(C)(C)C)[C@@H]1OCCS(C)(=O)=O
Product: C[C@H]1C[C@@H](c2ccncc2NC(=O)c2ccc(F)c(-c3c(F)cccc3F)n2)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1OCCS(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 48 %
Yield: 48 %

Procedure:
EDC (2.0 equiv.) and HOAt (2.0 equiv.) were added to a solution of (+/−)-tert-butyl (1R,2S,3S,5R)-5-(3-aminopyridin-4-yl)-3-methyl-2-(2-(methylsulfonyl)ethoxy)cyclohexylcarbamate (1.0 equiv.) and 6-(2,6-difluorophenyl)-5-fluoropicolinic acid (1.5 equiv.) in DMF (0.08 M). The mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined extracts were washed sequentially with 1M aqueous sodium hydroxide and brine, dried over sodium sulfate, filtered, concentrated and purified by ISCO SiO2 chromatography. Purification was completed via SFC (50% MeOH, 100 mL/min, IC column) to yield tert-butyl (1S,2R,3R,5S)-5-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-3-methyl-2-(2-(methylsulfonyl)ethoxy)cyclohexylcarbamate (48% yield, 99% ee) and tert-butyl (1R,2S,3S,5R)-5-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-3-methyl-2-(2-(methylsulfonyl) ethoxy)cyclohexylcarbamate (48% yield, 99% ee). LC/MS (m/z)=663.2 (MH+), Rt=0.88 min. 1H NMR (400 MHz, <cdcl3>) δ ppm 0.95 (d, J=6.75 Hz, 3 H), 1.45 (s, 8 H), 1.50-1.84 (m, 5 H), 2.80-2.95 (m, 1 H), 3.08 (s, 3 H), 3.14-3.29 (m, 1 H), 3.32-3.45 (m, 1 H), 3.56 (br. s., 1 H), 3.63-3.77 (m, 1 H), 3.95-4.08 (m, 1 H), 4.12 (q, J=7.12 Hz, 1 H), 5.36 (d, J=8.56 Hz, 1 H), 7.04-7.18 (m, 3 H), 7.50 (tt, J=8.47, 6.35 Hz, 1 H), 7.77 (t, J=8.56 Hz, 1 H), 8.33-8.46 (m, 2 H), 9.26 (s, 1 H), 9.81 (s, 1 H).
Reaction SMILES: C(OC(OCC(C)(C)C)N(C)C)C(C)(C)C.[Cl:17][C:18]1[CH:19]=[N:20][C:21](=[O:24])[NH:22][CH:23]=1.O[CH2:26][C:27]1[S:28][CH:29]=[CH:30][C:31]=1[CH3:32]>CN(C)C=O>[Cl:17][C:18]1[CH:19]=[N:20][C:21](=[O:24])[N:22]([CH2:26][C:27]2[S:28][CH:29]=[CH:30][C:31]=2[CH3:32])[CH:23]=1
Reactant: O=c1ncc(Cl)c[nH]1
Reactant: Cc1ccsc1CO
Agent: CN(C)C(OCC(C)(C)C)OCC(C)(C)C
Solvent: CN(C)C=O
Product: Cc1ccsc1Cn1cc(Cl)cnc1=O
Temperature: 90 °C
Yield: 28.9 %

Procedure:
N,N-Dimethylformamide dineopentyl acetal (2.70 ml) was added to a stirred suspension of 5-chloropyrimidin-2-one (783 mg) and 2-hydroxymethyl-3-methylthiophene (1.077 g) in dry N,N-dimethylformamide (15 ml) under nitrogen. The resulting solution was then heated at 90° C. under nitrogen. After 0.5 h the reaction mixture was evaporated to a dark brown crystalline solid (1.812 g). The solid was subjected to column chromatography on silica (70-230 mesh) (180 g) developing with chloroform-ethanol, 29:1. The resulting light brown crystalline solid (694 mg) was crystallised twice from acetone to give buff needles of the title thiophene (417 mg), m.p. 135°-145° C., λmax 230 nm (ε 16,420), 335 nm (ε 3,830), λinf 250 nm (ε 5,800).
Reaction SMILES: [CH:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([C:16]4[N:17]=[N:18][NH:19][N:20]=4)=[CH:15][C:10]=3[N:9]=[C:8]2[C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]3[N:33]=[C:32]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[O:40][CH3:41])[O:31][N:30]=3)=[CH:23][CH:22]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)Cl.[C:45]([OH:51])([C:47]([F:50])([F:49])[F:48])=[O:46].C([SiH](C(C)C)C(C)C)(C)C>>[CH:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([C:16]4[NH:17][N:18]=[N:19][N:20]=4)=[CH:15][C:10]=3[N:9]=[C:8]2[C:21]2[CH:22]=[CH:23][C:24]([O:27][CH2:28][C:29]3[N:33]=[C:32]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[O:40][CH3:41])[O:31][N:30]=3)=[CH:25][CH:26]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:45]([OH:51])([C:47]([F:50])([F:49])[F:48])=[O:46]
Reactant: COc1ccccc1-c1nc(COc2ccc(-c3nc4cc(-c5nn[nH]n5)ccc4n3C3CCCCC3)cc2)no1
Agent: CC(C)[SiH](C(C)C)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1-c1nc(COc2ccc(-c3nc4cc(-c5nnn[nH]5)ccc4n3C3CCCCC3)cc2)no1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Compound 37 from the preceding experiment was added to 2.0 mL of methylene chloride:TFA:triisopropylsilane (6:2:0.5). The mixture was shaken at rt for 20 min and was filtered. The resin was washed with methylene chloride (2×2 mL). The washings and filtrate were combined and concentrated on a rotary evaporator to afford 34 as a TFA salt (56 mg, 70% yield). ESI MS m/e 549 (M+1). The product was identical to that described in Example 5.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1.C1C(=O)N([Br:20])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:12])[CH:4]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)[Br:20]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)Cc1ccc(Cl)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(Br)c1ccc(Cl)cc1

Procedure:
2-Bromo-(p-chlorophenyl)-acetic acid methyl ester was prepared from (4-chlorophenyl)-acetic acid methyl ester (2.5 g, 13.5 mmol) and NBS (2.52 g, 14.1 mmol) in CCl4.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[CH:6]=[C:5]2[C:12]1[C:13](=[O:28])O[C:15](=[O:27])[C:16]=1[C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]([CH3:26])[CH:18]=1.[NH3:29].C[N:31](C=O)C>>[NH2:29][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[N:19]([CH3:26])[CH:18]=[C:17]2[C:16]1[C:15](=[O:27])[NH:31][C:13](=[O:28])[C:12]=1[C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[CH:2][CH:3]=2)[N:7]([CH3:11])[CH:6]=1
Reactant: CN(C)C=O
Reactant: Cn1cc(C2=C(c3cn(C)c4ccc(N)cc34)C(=O)OC2=O)c2ccccc21
Reactant: N
Product: Cn1cc(C2=C(c3cn(C)c4ccc(N)cc34)C(=O)NC2=O)c2ccccc21
Temperature: 140 °C

Procedure:
0.17 g of 3-(5-amino-1-methyl-3-indolyl)-4-(1-methyl-3-indolyl)furan-2,5-dione was treated with 4 ml of DMF and 30 ml of 33% aqueous ammonia and the mixture was heated at 140° C. for 4 hours. The cooled solution was filtered and the residue was washed with water to give 0.08 g of 3-(5-amino-1-methyl-3-indolyl)-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione , m.p. 254°-256° C.
Reaction SMILES: [CH:1]([C:4]1[S:13][C:12]2[NH:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[N:8]=[C:7]([NH2:18])[C:6]=2[N:5]=1)([CH3:3])[CH3:2].[F:19][C:20]1[CH:21]=[C:22]([CH2:26][CH2:27][C@H:28]2[CH2:33]N[CH2:31][CH2:30][NH:29]2)[CH:23]=[CH:24][CH:25]=1>>[F:19][C:20]1[CH:21]=[C:22]([CH2:26][CH2:27][C@@H:28]2[NH:29][CH2:30][CH2:31][N:18]([C:7]3[C:6]4[N:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[S:13][C:12]=4[NH:11][C:10]4[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=4[N:8]=3)[CH2:33]2)[CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)c1nc2c(s1)Nc1ccccc1N=C2N
Reactant: Fc1cccc(CC[C@H]2CNCCN2)c1
Product: CC(C)c1nc2c(s1)Nc1ccccc1N=C2N1CCN[C@@H](CCc2cccc(F)c2)C1
Yield: 54.7 %

Procedure:
By using a method similar to the method of Example 460, using 2-isopropyl-4H-3-thia-1,4,9-triaza-benzo[f]azulen-10-ylamine (0.566 g, 2.19 mmol) and (S)-2-[2-(3-fluoro-phenyl)-ethyl]-piperazine (0.457 g, 2.19 mmol) to give 0.539 g of the title compound as a solid: mass spectrum (ion spray): m/z=450 (M+1); Analysis for C25H28FN5S(0.2 H2O): calcd: C, 66.26; H, 6.32; N, 15.45; found: C, 65.96; H, 6.11; N, 15.31.
Reaction SMILES: [CH2:1]([OH:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7].[C:9]([N:12]1[C:16](=[O:17])[CH:15]=[CH:14][C:13]1=[O:18])(=[O:11])[NH2:10]>C(#N)C.[Cl-].[Zn+2].[Cl-]>[C:16]([O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][O:8][C:16](=[O:17])/[CH:15]=[CH:14]\[C:13](=[O:18])[NH:12][C:9](=[O:11])[NH2:10])(=[O:17])/[CH:15]=[CH:14]\[C:13](=[O:18])[NH:12][C:9](=[O:11])[NH2:10]
Reactant: NC(=O)N1C(=O)C=CC1=O
Reactant: OCCCCCCO
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC#N
Product: NC(=O)NC(=O)/C=C\C(=O)OCCCCCCOC(=O)/C=C\C(=O)NC(N)=O
Reaction time: 3 h

Procedure:
A mixture of 5.66 g of 1,6-hexanediol (0.048 moles), 12 g of N-carbamylmaleimide (0.086 moles) and 0.3 g of zinc chloride (0.0022 moles) in 70 mL of acetonitrile was heated to reflux. After 3 hours, a lot of solid material had been produced from the mixture. The mixture was filtered and the solids washed with acetonitrile and dried to afford 12.1 9 of 1,6-hexanediol bismaleurate.
Reaction SMILES: [CH2:1]([S:3][CH2:4][CH:5]([OH:8])[CH2:6][NH2:7])[CH3:2].[CH:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O>C1C=CC=CC=1>[C:10]1([CH:9]2[NH:7][CH2:6][CH:5]([CH2:4][S:3][CH2:1][CH3:2])[O:8]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCSCC(O)CN
Reactant: O=Cc1ccccc1
Solvent: c1ccccc1
Solvent: O
Product: CCSCC1CNC(c2ccccc2)O1
Temperature: 25 °C

Procedure:
Thirteen and five tenths (13.5) grams of 2-hydroxy-3-aminopropyl ethyl sulfide and 10.6 grams of benzaldehyde were combined in 100 milliliters of benzene and refluxed under a modified Dean-Stark apparatus until about 2 milliliters of water had been azetropically removed. The mixture was cooled to room temperature and the volume adjusted to 89.2 milliliters (4 milliliters=1 gram). Aliquots of this mixture were used in subsequent reactions.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[Cl-].[Al+3].[Cl-].[Cl-].[C:10]([N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])[CH3:11]>ClCCl>[C:10]([N:13]1[C:21]2[C:16](=[CH:17][C:18]([C:3](=[O:4])[CH2:2][Br:1])=[CH:19][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])[CH3:11]
Reactant: CC(=O)N1CCc2ccccc21
Reactant: O=C(Br)CBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)N1CCc2cc(C(=O)CBr)ccc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Bromoacetyl bromide (1.0 mL, 11.2 mmol) was slowly added to a suspension of aluminum chloride (3.7 g, 27.9 mmol) in dichloromethane (30 mL) and the reaction mixture was stirred for 20 min at rt. A solution of 1-acetylindoline (1.5 g, 9.3 mmol) in dichloromethane (10 mL) was slowly added and then the reaction mixture was heated at 55° C. for 1.5 h. The mixture was cooled and then quenched with cold water. The precipitate was filtered through a short pad of celite, washed with dichloromethane and water. The aqueous phase was extracted with dichloromethane. The combined organic extract was washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure to to give the product. Yield: 1.9 g (73%).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:10][CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][C:18]4[CH:23]=[CH:22][N:21]=[C:20]([C:24]5[CH:29]=[C:28]([O:30][CH3:31])[C:27]([O:32][CH3:33])=[C:26]([O:34][CH3:35])[CH:25]=5)[CH:19]=4)[CH2:13][CH2:12]3)=[CH:4][C:3]=2[O:2]1.[CH3:36][O:37][C:38]1[CH:39]=[C:40]([C:48]2[CH:55]=[CH:54][CH:53]=[CH:52][C:49]=2[CH2:50][Cl:51])[CH:41]=[C:42]([O:46][CH3:47])[C:43]=1[O:44][CH3:45]>>[ClH:51].[ClH:51].[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([N:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][C:18]4[CH:23]=[CH:22][N:21]=[C:20]([C:24]5[CH:25]=[C:26]([O:34][CH3:35])[C:27]([O:32][CH3:33])=[C:28]([O:30][CH3:31])[CH:29]=5)[CH:19]=4)[CH2:13][CH2:12]3)[CH2:50][C:49]3[CH:52]=[CH:53][CH:54]=[CH:55][C:48]=3[C:40]3[CH:41]=[C:42]([O:46][CH3:47])[C:43]([O:44][CH3:45])=[C:38]([O:37][CH3:36])[CH:39]=3)=[CH:4][C:3]=2[O:2]1
Reactant: COc1cc(-c2ccccc2CCl)cc(OC)c1OC
Reactant: COc1cc(-c2cc(CN3CCC(Nc4ccc5c(c4)OCO5)CC3)ccn2)cc(OC)c1OC
Product: COc1cc(-c2cc(CN3CCC(N(Cc4ccccc4-c4cc(OC)c(OC)c(OC)c4)c4ccc5c(c4)OCO5)CC3)ccn2)cc(OC)c1OC
Product: Cl

Procedure:
4-(3,4-Methylenedioxyphenylamino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine (119 mg) and 2-(3,4,5-trimethoxyphenyl)benzyl chloride (114 mg) were condensed in the same manner as described in Example 9. A free base obtained was converted to a dihydrochloroide to give the title compound as yellow powder.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][C:12]([NH2:15])([CH3:14])[CH3:13])[C:3]=1[C:4]#[N:5].[C:16]([O-:19])(O)=[O:17].[Na+].C(=O)([O-])ON1C(=O)CC([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)C1=O>C1COCC1.O>[NH2:1][C:2]1[C:3]([C:4]#[N:5])=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][CH2:11][C:12]([NH:15][C:16](=[O:17])[O:19][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([CH3:13])[CH3:14]
Reactant: O=C([O-])O
Reactant: CC(C)(N)COc1cccc(N)c1C#N
Reactant: O=C([O-])ON1C(=O)CC(Cc2ccccc2)C1=O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(COc1cccc(N)c1C#N)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.8 %

Procedure:
To a solution of 2-amino-6-(2-amino-2-methylpropoxy)benzonitrile (Example 24d, 30.5 g, 148.6 mmol) in THF/H2O (1:1, 400 mL) was added NaHCO3 (24.7 g, 294 mmol), followed by benzyl(2,5-dioxopyrrolidin-1-yl) carbonate (44.0 g, 176 mmol) at room temperature. The reaction was stirred at room temperature for 4 h then the organic layer was separated and the aqueous layer was extracted with EtOAc (2×). The combined organic layers were washed with brine and dried over MgSO4. After filtration, the solvent was evaporated and the crude oil was purified by chromatography on silica gel (eluent: 0-60% EtOAc in hexane) to give the title compound as yellow oil (44.8 g, 89%). 1H NR (400 MHz, DMSO-d6) δ 1.30 (s, 6H), 4.02 (s, 2H), 4.96 (s, 2H), 5.98 (s, 2H), 6.14 (d, J=8.0 Hz, 1H), 6.32 (dd, J=0.8, 8.4 Hz, 1H), 7.12 (t, J=8.4 Hz, 1H), 7.38-7.21 (m, 6H). MS 340 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:17]=[CH:16][C:11]3[O:12][CH2:13][CH2:14][O:15][C:10]=3[CH:9]=2)[O:5][C:4](=[O:18])[CH:3]=1.C(O)C.[CH2:22]1[CH2:26][CH:25]([SH:27])[CH2:24][CH2:23]1.N1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>C(O)(=O)C>[CH:25]1([S:27][CH:29]([C:3]2[C:4](=[O:18])[O:5][C:6]([C:8]3[CH:17]=[CH:16][C:11]4[O:12][CH2:13][CH2:14][O:15][C:10]=4[CH:9]=3)=[CH:7][C:2]=2[OH:1])[CH2:30][CH:31]2[CH2:33][CH2:32]2)[CH2:26][CH2:22][CH2:23][CH2:24]1
Reactant: O=c1cc(O)cc(-c2ccc3c(c2)OCCO3)o1
Reactant: SC1CCCC1
Reactant: C1CCNCC1
Solvent: CCO
Solvent: CC(=O)O
Product: O=c1oc(-c2ccc3c(c2)OCCO3)cc(O)c1C(CC1CC1)SC1CCCC1

Procedure:
The title compound was prepared by Method C using 4-hydroxy-6-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-2H-pyran-2-one (1.00 g, 4.06 mmol), ethanol (15 mL), cyclopropylmethylcarboxaldehyde (0.34 g, 4.06 mmol), cyclopentylthiol (0.83 g, 8.12 mmol), piperidine (1.0 mL), acetic acid (1.0 mL). m.p. 80-82° C.; 1H NMR (400 MHz, DMSO-d6) δ0.03 (m, 2H), 0.33 (m, 2H), 0.64 (m, 1H), 1.28-1.74 (m, 7H), 1.83-2.06 (m, 3H), 3.06 (m, 1H), 4.2 (m, 1H), 4.31 (m, 4H), 6.53 (s, 1H), 7.0 (d, 1H), 7.24 (d, 1H), 7.24 (dd, 2H).