Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)/[CH:3]=[CH:4]/[C@H:5]1[CH2:9][S:8][C:7](=[O:10])[N:6]1[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]#[N:18].C([Sn]([N:39]=[N+:40]=[N-:41])(CCCC)CCCC)CCC.C(OCC)(=O)C>C1(C)C=CC=CC=1>[OH:1][CH:2]([CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)/[CH:3]=[CH:4]/[C@H:5]1[CH2:9][S:8][C:7](=[O:10])[N:6]1[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]1[NH:41][N:40]=[N:39][N:18]=1
Reactant: N#CCCCCCCN1C(=O)SC[C@@H]1/C=C/C(O)Cc1ccccc1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C1SC[C@H](/C=C/C(O)Cc2ccccc2)N1CCCCCCc1nnn[nH]1
Yield: 62.3 %

Procedure:
To a solution of 4-4 (70 mg, 0.2 mmol) in 0.2 mL toluene was added tributyltin azide (0.27 mL, 1.0 mmol) and the resulting solution was stirred at reflux for 4 hours. Ethyl acetate (100 mL) was added and the solution was quenched with 5% aqueous KF (30 mL) and 1N HCl (30 mL). The layers were separated and the organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The compound was purified by flash chromatography using 0–5% MeOH/CH2Cl2 to yield 50 mg of 4-5 as a colorless oil. 1H NMR (400 MHz, CD3OD): δ7.29–7.17 (m, 5H), 5.81 (dd, 1H), 5.53 (dd, 1H), 4.38 (q, 1H), 4.33 (q, 1H), 3.45 (dd, 1H), 3.33 (m, 1H), 2.97 (m, 4H), 2.78 (m, 1H), 2.68 (m, 1H), 1.83–1.21 (m, 8H); MS (−ESI): m/z 400.2 (M−1)−.
Reaction SMILES: [CH2:1]([N:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH2:15][CH2:14]2)[CH3:5])[CH:2]=[CH2:3].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28](Cl)=[S:29])=[CH:23][CH:22]=1>O1CCOCC1>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]([N:16]2[C:17]3[C:13](=[CH:12][C:11]([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][N:4]([CH2:1][CH:2]=[CH2:3])[CH3:5])=[CH:19][CH:18]=3)[CH2:14][CH2:15]2)=[S:29])=[CH:23][CH:22]=1
Reactant: S=C(Cl)Oc1ccc(Cl)cc1
Reactant: C=CCN(C)CCCCCc1ccc2c(c1)CCN2
Solvent: C1COCCO1
Product: C=CCN(C)CCCCCc1ccc2c(c1)CCN2C(=S)Oc1ccc(Cl)cc1
Reaction time: 0.25 h
Yield: 42.9 %

Procedure:
130 mg (0.5 mmol) Allyl-[5-(2,3-dihydro-1H-indol-5-yl)-pentyl]-methyl-amine in 0.5 ml dioxane were treated with 0.072 ml (0.5 mmol) chlorothio-formicacid-O-(4-chlorophenyl)-ester at 15° C. The mixture was stirred for 15 min, concentrated and purified by column chromatography on silica gel with a gradient of CH2Cl2MeOH 99:1 to 97:3 to yield 92 mg 5-[5-(Allyl-methyl-amino)-pentyl]-2,3-dihydro-indole-1-carbothioic acid O-(4-chloro-phenyl)ester as colorless oil. The corresponding acetic acid salt was prepared by treatment with acetic acid in CH2Cl2 to yield 101 mg 5-[5-(Allyl-methyl-amino)-pentyl]-2,3-dihydro-indole-1-carbothioic acid O-(4-chloro-phenyl)esteracetic acid as light brown viscous oil, MS: 429 (MH+, 1Cl).
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]([CH3:19])([CH3:18])[C:15]([OH:17])=[O:16])=[CH:10][CH:9]=1)=[O:7].[CH2:20](O)[CH3:21]>>[Cl:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]([CH3:19])([CH3:18])[C:15]([O:17][CH2:20][CH3:21])=[O:16])=[CH:10][CH:9]=1)=[O:7]
Reactant: CCO
Reactant: CC(C)(C(=O)O)c1ccc(C(=O)CCCCl)cc1
Agent: Cl
Product: CCOC(=O)C(C)(C)c1ccc(C(=O)CCCCl)cc1
Yield: 97 %

Procedure:
Add anhydrous hydrogen chloride gas (18.0 g) to anhydrous ethanol DB (210 g) by purging the solution. Add this hot solution (60° C.) to a solution of 2-[4-(4-chloro-butyryl)-phenyl]-2-methyl-propionic acid (31 g, 115.6 mmol) and reflux under a nitrogen atmosphere for 2.5 hours. Evaporate the solvent in vacuo, dissolve the residue in methylene chloride (150 mL) and wash with water (2×100 mL). Dry (MgSO4), filter through silica gel, washing the gel with methylene chloride (250 mL). Combine the organic washings and evaporate the solvent in vacuo to give the title compound as a colorless oil (33.3 g, 97%).
Reaction SMILES: C(OC([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:17][N:18]([CH2:29][C:30]1([CH2:33][CH2:34][N:35]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:32][CH2:31]1)[CH:19]1[C:28]2[N:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:22][CH2:21][CH2:20]1)=O)(C)(C)C.O.NN>C(O)C>[NH2:35][CH2:34][CH2:33][C:30]1([CH2:29][N:18]([CH2:17][C:9]2[NH:8][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=2)[CH:19]2[C:28]3[N:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH2:22][CH2:21][CH2:20]2)[CH2:32][CH2:31]1
Reactant: CC(C)(C)OC(=O)n1c(CN(CC2(CCN3C(=O)c4ccccc4C3=O)CC2)C2CCCc3cccnc32)nc2ccccc21
Agent: NN
Solvent: O
Solvent: CCO
Product: NCCC1(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)CC1
Yield: 51.9 %

Procedure:
To a solution of 2-{[{1-[2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-cyclopropylmethyl}-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzimidazole-1-carboxylic acid tert-butyl ester (0.121 g, 0.20 mmol) in ethanol (4 mL) was added hydrazine monohydrate (0.20 mL, 4.12 mmol) and the resultant mixture was stirred at room temperature overnight. The mixture was filtered through filter paper and concentrated. Purification of the crude material by column chromatography on silica gel (20:1:1 CH2Cl2—CH3OH—NH4OH) provided 39 mg (50%) of the free base of the title compound as a yellow oil.
Reaction SMILES: [CH2:1]([CH:11]([CH2:24][CH2:25][CH2:26]/[CH:27]=[CH:28]\[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH:12]([OH:23])[CH2:13][CH2:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[Br:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40](O)=[O:41].CCN=C=NCCCN(C)C.Cl.C(N(C(C)C)CC)(C)C>ClCCl.CN(C1C=CC=CN=1)C>[Br:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40]([O:23][CH:12]([CH:11]([CH2:1][CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:24][CH2:25][CH2:26]/[CH:27]=[CH:28]\[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:13][CH2:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:41]
Reactant: CCCCC/C=C\CCCC(O)C(CCC/C=C\CCCCC)CCC/C=C\CCCCC
Reactant: O=C(O)CCCCCBr
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCC/C=C\CCCC(CCC/C=C\CCCCC)C(CCC/C=C\CCCCC)OC(=O)CCCCCBr
Temperature: 25 °C
Yield: 93.5 %

Procedure:
To a solution of (6Z,16Z)-12-((Z)-dec-4-enyl)docosa-6,16-dien-11-ol 8 (2.4 g, 5.2 mmol), 6-bromohexanoic acid (1.5 g, 7.8 mmol), EDCI hydrochloride (1.5 g, 7.8 mmol), diisopropylethylamine (2.0 g, 15.6 mmol) in anhydrous dichloromethane (25 mL) was added dimethylaminopyridine (15 mg). The solution was refluxed for 2 hours, cooled to room temperature and concentrated in vacuo to dryness. The reaction mixture was purified by column chromatography on silica gel 60 (2″ W×10″ L; eluted with 5% EtOAc/Hex) to afford (6Z,16Z)-12-((Z)-dec-4-enyl)docosa-6,16-dien-11-yl 6-bromohexanoate 10 as a colorless oil (3.1 g, 94%). Rf 0.5 (10% EtOAc-Hexanes).
Reaction SMILES: [CH3:1][O-:2].[Na+].[NH2:4][C:5]1[N:10]=[C:9](F)[N:8]=[C:7]([O:12][C:13]([F:16])([F:15])[F:14])[N:6]=1>CO>[NH2:4][C:5]1[N:10]=[C:9]([O:2][CH3:1])[N:8]=[C:7]([O:12][C:13]([F:16])([F:15])[F:14])[N:6]=1
Reactant: Nc1nc(F)nc(OC(F)(F)F)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc(N)nc(OC(F)(F)F)n1
Reaction time: 1 h

Procedure:
9.1 g (0.05 mol) of 30% strength sodium methylate were added to a mixture of 10 g (0.05 mol) of 2-amino-4-fluoro-6-trifluoromethoxy-1,3,5-triazine in 100 ml of methanol at 0° C. in the course of 15 minutes while stirring. Stirring was carried out for one hour at 0° C., after which the mixture was evaporated down under reduced pressure, the residue was taken up in methylene chloride and the solution was extracted with water. Drying and evaporating down gave 10.5 g (99% of theory) of the title compound of melting point 96°-101° C.
Reaction SMILES: CO[C:3](=[O:37])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C@@H:15]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[NH:16][S:17]([C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=2)(=[O:19])=[O:18])=[CH:10][CH:9]=1.[NH:38]1[CH2:43][CH2:42][CH2:41][N:40]=[C:39]1[NH2:44]>CN(C)C=O>[C:33]([O:32][C:30](=[O:31])[C@@H:15]([NH:16][S:17]([C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=1)(=[O:19])=[O:18])[CH2:14][C:11]1[CH:12]=[CH:13][C:8]([O:7][CH2:6][CH2:5][CH2:4][C:3](=[O:37])[NH:44][C:39]2[NH:40][CH2:41][CH2:42][CH2:43][N:38]=2)=[CH:9][CH:10]=1)([CH3:34])([CH3:36])[CH3:35]
Reactant: NC1=NCCCN1
Reactant: COC(=O)CCCOc1ccc(C[C@H](NS(=O)(=O)c2ccc3ccccc3c2)C(=O)OC(C)(C)C)cc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)[C@H](Cc1ccc(OCCCC(=O)NC2=NCCCN2)cc1)NS(=O)(=O)c1ccc2ccccc2c1
Reaction time: 8 h

Procedure:
145 mg of 4{-4-[(2S)-2-tert-butoxycarbonyl-2-(naphthalene-2-sulfonylamino)-ethyl]-phenoxy}-butyric acid methyl ester were dissolved in 2 ml of DMF (dimethylformamide) and 134 mg of 1,4,5,6-tetrahydropyrimidin-2-ylamine were added. The reaction mixture was stirred overnight, and the solvent was removed in vacuo. The residue was chromatographed on silica gel eluting with dichloromethane, followed by dichloromethane/methanol (10/1). Yield 127 mg. Rf (dichloromethane/methanol/water/acetic acid (85/15/1.5/1.5)): 0.63. MS (ES+): m/e=595.2 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[C:10]([N:21]2[S:25](=[O:27])(=[O:26])[NH:24][C:23](=[O:28])[CH2:22]2)=[C:11]([F:20])[C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[C:14](Br)[CH:13]=2)C1C=CC=CC=1.[CH3:29][C:30]([CH3:45])([CH2:33]/[CH:34]=[CH:35]/B1OC(C)(C)C(C)(C)O1)[CH2:31][OH:32]>>[F:20][C:11]1[C:12]2[C:17](=[CH:16][CH:15]=[C:14]([CH2:35][CH2:34][CH2:33][C:30]([CH3:45])([CH3:29])[CH2:31][OH:32])[CH:13]=2)[CH:18]=[C:9]([OH:8])[C:10]=1[N:21]1[S:25](=[O:26])(=[O:27])[NH:24][C:23](=[O:28])[CH2:22]1
Reactant: O=C1CN(c2c(OCc3ccccc3)cc3ccc(Br)cc3c2F)S(=O)(=O)N1
Reactant: CC(C)(CO)C/C=C/B1OC(C)(C)C(C)(C)O1
Product: CC(C)(CO)CCCc1ccc2cc(O)c(N3CC(=O)NS3(=O)=O)c(F)c2c1

Procedure:
The title compound is prepared analogously to Example 9, Steps A and B, starting from 5-(3-benzyloxy-7-bromo-1-fluoronaphthalen-2-yl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one and (E)-2,2-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pent-4-en-1-ol, Retention time=1.16 min (Method A); MS (M−H)−=409.
Reaction SMILES: [CH3:1][C:2]([CH3:17])([O:4][C:5]([NH:7][C:8]1[S:9][CH:10]=[C:11]([CH2:13][C:14]([OH:16])=O)[N:12]=1)=[O:6])[CH3:3].[CH2:18]([O:20][C:21](=[O:29])[CH2:22][C:23]1[N:24]=[C:25]([NH2:28])[S:26][CH:27]=1)[CH3:19].F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(C(C)C)CC)(C)C>CN(C)C1C=CN=CC=1.ClCCl>[CH3:17][C:2]([CH3:1])([O:4][C:5]([NH:7][C:8]1[S:9][CH:10]=[C:11]([CH2:13][C:14]([NH:28][C:25]2[S:26][CH:27]=[C:23]([CH2:22][C:21]([O:20][CH2:18][CH3:19])=[O:29])[N:24]=2)=[O:16])[N:12]=1)=[O:6])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1nc(CC(=O)O)cs1
Reactant: CCOC(=O)Cc1csc(N)n1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)Cc1csc(NC(=O)Cc2csc(NC(=O)OC(C)(C)C)n2)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 2-[[1,1-Dimethylethoxy]carbonylamino]-4-thiazoleacetic acid (1.7 g) (Chem. Pharm. Bull. 1993, 41, 758), 2-amino-4-thiazoleacetic acid ethyl ester (1.35 g), 4-[dimethylamino]pyridine (0.8 g) and bromo-tris(pyrrolidino)phosphonium hexafluorophosphate (3.3 g) in dry dichloromethane (50 ml) was treated with diisopropylethylamine (2.4 ml). The mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with aqueous sodium bicarbonate and diluted with ethyl acetate. The organic solution was washed with brine and 2M HCl. The solution was dried (MgSO4) and evaporated under reduced pressure. Purification was by chromatography eluting with 30% ethyl acetate in isohexane. Yield 0.8 g.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=O)[CH2:11][CH2:10]3)[CH:2]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:27])=CC=1>C1(C)C=CC=CC=1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[S:27])[CH2:11][CH2:10]3)[CH:2]=1
Reactant: O=C1CCc2cc(-c3cccnc3)ccc2N1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: S=C1CCc2cc(-c3cccnc3)ccc2N1

Procedure:
A mixture of 6-Pyridin-3-yl-3,4-dihydro-1H-quinolin-2-one (395 mg, 1.76 mmol) and Lawessons reagent (356 mg, 0.88 mmol) was refluxed in 30 ml toluene for 2 h. After evaporation of the solvent under reduced pressure, the residue was purified by flash chromatography on silica gel (hexanes/ethyl acetate, 3/7, Rf=0.31) which gave 6-Pyridin-3-yl-3,4-dihydro-1H-quinoline-2-thione as yellow plates (63 mg, 0.26 mmol, 15%), mp (hexanes/ethyl acetate) 267° C. 1H-NMR (500 MHz, DMSO-d6): δ=2.87 (m, 2H), 2.97 (m, 2H), 7.20 (d, 3J=8.2 Hz, 1H), 7.46 (dd, 3J=7.9 Hz, 3J=4.6 Hz, 1H), 7.59 (dd, 3J=8.2 Hz, 4J=1.9 Hz, 1H), 7.62 (d, 4J=1.9 Hz, 1H), 8.04 (m, 1H), 8.53 (dd, 3J=4.7 Hz, 4J=1.6 Hz, 1H), 8.87 (d, 4J=2.2 Hz, 1H), 12.30 (s, 1H). MS m/z=241.05 (MH+).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.C1CCN2C(=NCCC2)CC1.Cl.[N:33]1([CH:38]2[CH2:42][CH2:41][NH:40][CH2:39]2)[CH:37]=[CH:36][N:35]=[N:34]1>N1C=CC=CC=1>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:40]4[CH2:41][CH2:42][CH:38]([N:33]5[CH:37]=[CH:36][N:35]=[N:34]5)[CH2:39]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: c1cn(C2CCNC2)nn1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3CCC(n4ccnn4)C3)c(F)cc2c1=O
Temperature: 7580 °C

Procedure:
A mixture of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid (138.5 mg, 0.486 mmol), DBU (190 mg, 1.25 mmol), and 3-(1,2,3-triazol-1-yl)pyrrolidine hydrochloride (216 mg, 1.25 mmol) in pyridine (8 ml) was heated for 20 h at 7580° C. and then pyridine was removed under vacuum. The residue was diluted with acetonitrile. The precipitated solid was washed with acetonitrile, ether and dried at 40° C. Yield: 65 mg (33%), m.p. 244°-246° C. (dec). 1H NMR (TFA) δ: 1.5 (m, 4H), 2.8 (m, 2H), 4.5 (m, 4H), 4.75 (bs, 1H), 5.8 (bs, 1H), 8.15 (d, 1H), 8.6 (s, 1H), 8.7 (s, 1H), 9.25 (s, 1H).
Reaction SMILES: [H-].[Na+].[CH3:3]C(N(C)C)=O.[F:9][C:10]1[CH:28]=[CH:27][C:13]([CH2:14][N:15]2[C:20]3[N:21]=[CH:22][CH:23]=[CH:24][C:19]=3[C:18](=[O:25])[N:17]=[C:16]2[NH2:26])=[CH:12][CH:11]=1.CI>O>[F:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:14][N:15]2[C:20]3[N:21]=[CH:22][CH:23]=[CH:24][C:19]=3[C:18](=[O:25])[N:17]([CH3:3])[C:16]2=[NH:26])=[CH:27][CH:28]=1
Reactant: CC(=O)N(C)C
Reactant: Nc1nc(=O)c2cccnc2n1Cc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: Cn1c(=O)c2cccnc2n(Cc2ccc(F)cc2)c1=N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 0.4 g. of sodium hydride in 60 ml. of dimethylacetamide is added 2.5 g. of 1-(4'-fluorobenzyl)-2-amino-pyrido[2,3-d]pyrimidin-4(1H)-one while maintaining the system under nitrogen. After stirring for one hour at room temperature, the mixture is treated by addition of 1.0 ml. of methyliodide. The resulting mixture is stirred at 20°C. for 15 hours. A small amount of water (ca 1.0 ml.) is then added and the mixture evaporated in vacuo. The residue is treated with ice/water and the resulting precipitate is recovered by filtering, washed with water and dried. The dried precipitate is then dissolved in methylene chloride, treated with charcoal and filtered through neutral alumina. The filtrate is concentrated in vacuo and ether added to obtain on crystallization 1-(4'-fluorobenzyl)-2,3-dihydro-2-imino-3-methyl-pyrido[2,3-d]pyrimidin-4(1H)-one
Reaction SMILES: C[O:2][C:3](=[O:32])[C@H:4]([NH:12][C:13]([O:15][CH2:16][C:17]1[NH:18][C:19]2[C:24]([CH:25]=1)=[CH:23][C:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[CH:21][CH:20]=2)=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O.[OH-].[Li+]>CO.O>[C:26]1([C:22]2[CH:23]=[C:24]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17]([CH2:16][O:15][C:13]([NH:12][C@H:4]([CH2:5][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:3]([OH:32])=[O:2])=[O:14])=[CH:25]3)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: COC(=O)[C@@H](Cc1ccccc1)NC(=O)OCc1cc2cc(-c3ccccc3)ccc2[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(N[C@H](Cc1ccccc1)C(=O)O)OCc1cc2cc(-c3ccccc3)ccc2[nH]1
Temperature: 50 °C
Yield: 24.4 %

Procedure:
A solution of (R)-2-(5-phenyl-indol-2-ylmethoxycarbonylamino)-3-phenyl-propionic acid methyl ester 46 (0.195 g, 0.455mmole) in methanol (20 ml) was treated with a solution of lithium hydroxide monohydrate (23 mg, 0.55 mmole) in water (1 ml) and heated to 50° C. for 7 hrs, cooled to room temperature, acidified, evaporated, extracted with EtOAc, washed, dried, and evaporated. The residue was purified by chromatography to give about 46 mg of (R)-2-(5-phenyl-indol-2-ylmethoxycarbonylamino)-3-phenyl-propionic acid 47, mp. 168–174°.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][C:13](=[O:19])[NH:14]3)=[CH:6][CH:5]=1.[N:22]1([CH2:27][CH2:28][NH:29][C:30]([C:32]2[C:36]([CH3:37])=[C:35]([CH:38]=O)[NH:34][C:33]=2[CH3:40])=[O:31])[CH:26]=[CH:25][N:24]=[N:23]1>C(O)C.N1CCCCC1>[N:22]1([CH2:27][CH2:28][NH:29][C:30]([C:32]2[C:36]([CH3:37])=[C:35]([CH:38]=[C:12]3[C:11]4[C:15](=[CH:16][CH:17]=[CH:18][C:10]=4[C:7]4[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:20])[F:21])=[CH:9][CH:8]=4)[NH:14][C:13]3=[O:19])[NH:34][C:33]=2[CH3:40])=[O:31])[CH:26]=[CH:25][N:24]=[N:23]1
Reactant: O=C1Cc2c(cccc2-c2ccc(OC(F)(F)F)cc2)N1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCn1ccnn1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4ccc(OC(F)(F)F)cc4)c32)c(C)c1C(=O)NCCn1ccnn1
Temperature: 25 °C
Reaction time: 72 h
Yield: 37 %

Procedure:
To a solution of 4-(4-trifluoromethoxy-phenyl)-1,3-dihydro-indol-2-one (73.3 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)amide (67.9 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 2,4-dimethyl-5-[2-oxo-4-(4-trifluoromethoxy-phenyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-ylethyl)amide as a yellow solid (49.6 mg, 37%).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]2[C:3]=1[C:4](=O)[C:5](=O)[NH:6]2.[F:14][C:15]1[CH:28]=[CH:27][C:18]([CH2:19][C:20]2[N:21]([NH2:26])[C:22]([NH2:25])=[N:23][N:24]=2)=[CH:17][CH:16]=1>C(O)CO.O>[F:14][C:15]1[CH:28]=[CH:27][C:18]([CH2:19][C:20]2[N:21]3[C:22]([N:25]=[C:5]4[C:4](=[N:26]3)[C:3]3[C:7](=[C:8]([CH3:11])[CH:9]=[CH:10][C:2]=3[CH3:1])[NH:6]4)=[N:23][N:24]=2)=[CH:17][CH:16]=1
Reactant: Cc1ccc(C)c2c1NC(=O)C2=O
Reactant: Nc1nnc(Cc2ccc(F)cc2)n1N
Solvent: O
Solvent: OCCO
Product: Cc1ccc(C)c2c1[nH]c1nc3nnc(Cc4ccc(F)cc4)n3nc12
Temperature: 125 °C
Reaction time: 18 h

Procedure:
According to the general cyclization procedure (for Example 27), 0.60 mmol of 4,7-dimethyl-1H-indole-2,3-dione (105 mg) and 0.70 mmol of (4-fluoro-benzyl)-[1,2,4]triazole-3,4-diamine (145 mg) in 2 mL of ethylene glycol was stirred at 125° C. overnight (18 hr). The mixture was cooled to room temperature, diluted with water (10 mL), stirred for 15 min. The precipitated product was collected by filtration, washed with MeOH+water 1:1. Dried on high vacuum. The crude product (187 mg) was suspended in anhydrous ethanol (6 mL), heated to reflux, sonicated while hot, allowed to cool overnight, filtered, washed with ice-cold methanol, filtered and dried on high vacuum.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([OH:20])[CH:17]=[C:16]([C:21]#[C:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[CH:15]=2)=[CH:9][C:8]=1[Cl:30])[CH3:2].[N:32]1([CH2:38][CH2:39][CH2:40]O)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[CH2:1]([O:3][C:4](=[O:31])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([O:20][CH2:40][CH2:39][CH2:38][N:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)[CH:17]=[C:16]([C:21]#[C:22][C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)[CH:15]=2)=[CH:9][C:8]=1[Cl:30])[CH3:2]
Reactant: OCCCN1CCCCC1
Reactant: CCOC(=O)COc1ccc(Sc2cc(O)cc(C#Cc3ccc(Cl)cc3)c2)cc1Cl
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccc(Cl)cc3)cc(OCCCN3CCCCC3)c2)cc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
[{2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-hydroxy-phenylsulfanyl]-phenoxy}-acetic acid ethyl ester (0.4 g; 0.85 mmol), 3-piperidin-1-yl-propan-1-ol (0.12 g; 0.85 mmol) and tributylphosphine (0.37 mL; 1.5 mmol) were dissolved in THF (50 mL) in a dried reaction flask under an atmosphere of nitrogen. 1,1′-(Azodicarbonyl)dipiperidine (0.38 g; 1.5 mmol) dissolved in THF (25 mL) was added to the reaction mixture, which was stirred at room temperature for 16 h. The reaction mixture was evaporated to dryness and 5% aqueous citric acid and ethyl acetate was added. The organic phase was separated, dried, evaporated to dryness, and purified by prep HPLC (method A). Yield: 275 mg. HPLC-MS: m/z: 598.0 (M+); Rt: 2.3 min.
Reaction SMILES: [OH-].[Na+].C([O:6][C:7]1[CH:8]=[CH:9][C:10]2[O:15][CH2:14][CH:13]([C:16]([O:18]CC)=[O:17])[O:12][C:11]=2[CH:21]=1)(=O)C>CO>[OH:6][C:7]1[CH:8]=[CH:9][C:10]2[O:15][CH2:14][CH:13]([C:16]([OH:18])=[O:17])[O:12][C:11]=2[CH:21]=1
Reactant: CCOC(=O)C1COc2ccc(OC(C)=O)cc2O1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C1COc2ccc(O)cc2O1
Temperature: 25 °C
Reaction time: 6 h
Yield: 85 %

Procedure:
Under a nitrogen atmosphere, slowly add 75 mmol of a 10% aqueous sodium hydroxide solution to a solution of 2 g (7.5 mmol) of ethyl 7-acetoxy-2,3-dihydro-1,4-benzodioxin-2-carboxylate in 20 cm3 of methanol. Stir at room temperature for 6 hours and then, after concentrating under reduced pressure, acidify the mixture with a 2N hydrochloric acid solution. Extract with diethyl ether the acid which precipitates, then, after drying and concentration to dryness, wash the resulting acid with methylene chloride. 7-Hydroxy-2,3-dihydro-1,4-benzodioxin-2-carboxylic acid is thereby obtained in a yield of 85%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:12]([OH:17])[CH2:13][CH2:14][CH2:15][CH3:16])[CH:5]=[CH:6][C:7]=1[CH:8]=[C:9]([CH3:11])[CH3:10]>[Pd].CO>[F:1][C:2]1[CH:3]=[C:4]([CH:12]([OH:17])[CH2:13][CH2:14][CH2:15][CH3:16])[CH:5]=[CH:6][C:7]=1[CH2:8][CH:9]([CH3:10])[CH3:11]
Reactant: CCCCC(O)c1ccc(C=C(C)C)c(F)c1
Agent: [Pd]
Solvent: CO
Product: CCCCC(O)c1ccc(CC(C)C)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.2 %

Procedure:
A mixture of 1-[3-fluoro-4-(2-methyl-1-propenyl)phenyl]pentanol (300 mg) and 10% palladium on carbon (90 mg) in methanol (10 ml) was stirred under hydrogen atmosphere for 30 minutes at room temperature. Catalyst was removed by filtration and the solvent was evaporated. The residue was chromatographed on silica gel column eluting with a mixture of hexane and ethyl acetate (85:15) to give 1-(3-fluoro-4-isobutylphenyl)pentanol (167 mg) as an oil.