Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC1C=C(CN)C=NC=1.[N:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH2:17])=[CH:12][CH:11]=1.[CH3:18][C:19]1[N:20]=[C:21]([N:27]2[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][CH2:34][C:35]([F:38])([F:37])[F:36])[C:28]2=[O:39])[S:22][C:23]=1[C:24](O)=[O:25]>>[CH3:18][C:19]1[N:20]=[C:21]([N:27]2[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][CH2:34][C:35]([F:36])([F:37])[F:38])[C:28]2=[O:39])[S:22][C:23]=1[C:24]([NH:17][CH2:16][C:13]1[CH:14]=[CH:15][N:10]=[CH:11][CH:12]=1)=[O:25]
Reactant: NCc1ccncc1
Reactant: Cc1nc(N2CCN(CCCC(F)(F)F)C2=O)sc1C(=O)O
Agent: NCc1cncc(F)c1
Product: Cc1nc(N2CCN(CCCC(F)(F)F)C2=O)sc1C(=O)NCc1ccncc1
Yield: 42 %

Procedure:
Following the procedure as describe in Example 12, making variations as required to replace (5-fluoropyridin-3-yl)methanamine with pyridin-4-ylmethanamine to react with 4-methyl-2-(2-oxo-3-(4,4,4-trifluorobutyl)imidazolidin-1-yl)thiazole-5-carboxylic acid in place of 2-(3-(cyclopropylmethyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid in 42% yield: mp 178-181° C. (dichloromethane/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.55 (s, 2H), 7.24-7.22 (m, 2H), 6.20-6.16 (m, 1H), 4.57 (d, J=5.9 Hz, 2H), 4.16-4.10 (m, 2H), 3.63-3.58 (m, 2H), 3.41-3.39 (m, 2H), 2.61 (s, 3H), 2.19-2.10 (m, 2H), 1.91-1.83 (m, 2H); MS (ES+) m/z 428.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[OH:26][CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C(N(C(C)C)CC)(C)C.ClCl>CS(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]([CH:8]=[CH:7][C:3]=1[C:4]([N:30]1[CH2:31][CH2:32][CH:27]([OH:26])[CH2:28][CH2:29]1)=[O:6])[C:11]([NH:13][CH:14]([C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=2[N:17]=1)[CH3:15])=[O:12]
Reactant: CC(NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Reactant: OC1CCNCC1
Agent: ClCl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(NC(=O)c1ccc(C(=O)N2CCC(O)CC2)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1d from rac.-2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, 4-hydroxypiperidine, PFTU, and diisopropylethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 3.97 minutes; C22H22Cl2N4O3 (461.35); mass spectrum: (M−H)−=460/462/464 (chlorine isotope).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:5][N:4]=1)#[N:2]>CO.[Pd]>[NH2:2][CH2:1][C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:5][N:4]=1
Reactant: COC(=O)CCCc1ccnc(C#N)c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCCc1ccnc(CN)c1

Procedure:
2-Cyano-4-(3-methoxycarbonylpropyl)pyridine (0.83 g) is hydrogenated at 3 atmospheres for 3 hours in 9 ml of methanol with 0.4 g of 10% palladium on charcoal. Filtration, evaporation, and preparative thin layer chromatography on silica gel with 1:1 methanol-ethyl acetate yields 2-aminomethyl-4-(3-methoxycarbonylpropyl)pyridine; Rf, 0.37 (EtOAc-MeOH 1:1, 1% NH4OH); NMR (CDCl3) 3.67 (s, 3 H), 4.15 (s, 2 H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[CH2:4][C:5]([CH2:7]Cl)=O.[C:10]([NH:13][C:14]([NH2:16])=[S:15])(=[O:12])[CH3:11]>>[C:10]([NH:13][C:14]1[S:15][CH:7]=[C:5]([CH2:4][C:3]([O:2][CH3:1])=[O:9])[N:16]=1)(=[O:12])[CH3:11]
Reactant: COC(=O)CC(=O)CCl
Reactant: CC(=O)NC(N)=S
Product: COC(=O)Cc1csc(NC(C)=O)n1
Reaction time: 23 h

Procedure:
Methyl-4-chloroacetoacetate (11.54ml), N-acetylthiourea (11.8g) and 4A molecular sieves (10g) were stirred in dry, distilled dimethylformamide (DMF) (50ml) at 50° C., for 23h. After this time the reaction appeared complete by t.1.c. The mixture was cooled and filtered through a dicalite pad. The residue was washed with DMF and tetrahydrofuran and the resultant filtrates diluted with water. This solution was washed five times with ethyl acetate; the organic washes were combined, dried, filtered and evaporated to give a yellow oil. This was triturated under water whereupon a white precipitate formed. This was cooled to complete and the resultant solid filtered off, washed with cold water and dried to give the desired product (14.63g) as a white crystalline solid, m.p. 122°-123° C. (from ethyl acetate-hexane); υ max (nujol) 3175 (w), 1740, 1655, 1560 and 1543cm-1 ; δ[(CD3)2SO, 60MHz]2.1 (3H, s). 3.6 (3H. s). 3.7 (2 H. s). and 6.9 (1H. s). (Found: C, 44.9; H, 4.7; N, 13.4; S, 15.3. C8H10N2O3S requires: C, 44.9; H, 4.7; N, 13.1; S, 15.0%). The mother liquors were concentrated to low volume and cooled to yield a second crop of the desired material (2.54g) which was slightly less pure by NMR.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[N:12]([C:14]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:13]=[C:8]3[C:9]2=[C:4]([CH2:5][CH2:6][N:7]3[CH2:33][CH3:34])[N:3]=1.[C:35]1([C@H:41]([NH:43][C:44]([NH2:46])=[O:45])[CH3:42])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C.C(Cl)Cl>[CH2:33]([N:7]1[CH2:6][CH2:5][C:4]2[N:3]=[C:2]([NH:46][C:44]([NH:43][C@@H:41]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH3:42])=[O:45])[CH:11]=[C:10]3[N:12]([C:14]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)([C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:13]=[C:8]1[C:9]=23)[CH3:34]
Reactant: C[C@@H](NC(N)=O)c1ccccc1
Reactant: CCN1CCc2nc(Cl)cc3c2c1nn3C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: COc1ccc(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Product: CCN1CCc2nc(NC(=O)N[C@H](C)c3ccccc3)cc3c2c1nn3C(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
7-chloro-3-ethyl-1-trityl-1,3,4,5-tetrahydropyrazolo[3,4,5-de][1,6]naphthyridine (35 mg, 0.075 mmol), (R)-1-(1-phenylethyl)urea (18.5 mg, 0.113 mmol), cesium carbonate (73.6 mg, 0.226 mmol) and BrettPhos pre-catalyst (6.8 mg) were charged in a 1 dram vial, evacuated and backfilled with nitrogen and taken in 1,4-dioxane (0.4 mL) and heated reaction at 100° C. for 1 hour. The reaction mixture was diluted with DCM, washed with water, brine, dried with sodium sulfate and concentrated. Purification of the residue by flash column (0-75% EtOAc-hexanes) gave (R)-1-(3-ethyl-1-trityl-1,3,4,5-tetrahydropyrazolo[3,4,5-de][1,6]naphthyridin-7-yl)-3-(1-phenylethyl)urea. MS ESI calc'd. for C38H36N6O [M+H]+ 593. found 593.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:17]2[O:16][CH:15]([CH2:18]OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:14][C:13]=2[CH:12]=[C:11]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:10]=1.[CH3:36][NH2:37]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:17]2[O:16][CH:15]([CH2:18][NH:37][CH3:36])[CH2:14][C:13]=2[CH:12]=[C:11]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:10]=1
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(-c4ccccc4)cc(-c4ccc(F)cc4F)c3O2)cc1
Product: CNCC1Cc2cc(-c3ccccc3)cc(-c3ccc(F)cc3F)c2O1

Procedure:
The title compound was prepared (0.047 g, 59%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-{[7-(2,4-difluorophenyl)-5-phenyl-2,3-dihydro-1-benzofuran-2-yl]methyl}4-methylbenzenesulfonate (0.10 g, 0.20 mmol) and methylamine (0.30 g, 9.8 mmol). mp 188-191° C.
Reaction SMILES: Cl[CH:2]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])=[CH:10][CH:9]=1)[C:3]([OH:5])=[O:4].[SH-:21].[Na+].Cl>C(O)C>[SH:21][CH:2]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])=[CH:10][CH:9]=1)[C:3]([OH:5])=[O:4]
Reactant: O=C(O)C(Cl)CCc1ccc(-c2ccccc2Cl)cc1
Reactant: [SH-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=C(O)C(S)CCc1ccc(-c2ccccc2Cl)cc1

Procedure:
A mixture of 0.05 moles of α-chloro-γ-(2'-chloro-4-biphenylyl) butyric acid and 5 g. of sodium hydrosulfide in 100 ml. of absolute ethanol and under a nitrogen atmosphere is stirred for 15 hours. The mixture is then acidified with 6 N hydrochloric acid. The solvent is removed in vacuo and the residue is extracted into ether, washed with water, saturated sodium chloride solution, dried and evaporated to dryness to obtain α-mercapto-γ-(2'-chloro-4-biphenylyl)butyric acid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:66])[C@@H:4]([NH:20][C:21]([CH:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([CH3:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][N:24]1[S:53]([C:56]1[S:60][C:59]([NH:61][C:62](=[O:64])[CH3:63])=[N:58][C:57]=1[CH3:65])(=[O:55])=[O:54])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.I[CH2:68][CH:69]1[CH2:73][CH2:72][CH2:71][CH2:70]1>>[CH3:1][O:2][C:3](=[O:66])[C@@H:4]([NH:20][C:21]([CH:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:38]=[CH:39][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([CH3:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:41][CH:42]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][N:24]1[S:53]([C:56]1[S:60][C:59]([N:61]([C:62](=[O:64])[CH3:63])[CH2:68][CH:69]2[CH2:73][CH2:72][CH2:71][CH2:70]2)=[N:58][C:57]=1[CH3:65])(=[O:55])=[O:54])=[O:22])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:10][CH:11]=1
Reactant: ICC1CCCC1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1S(=O)(=O)c1sc(NC(C)=O)nc1C)O[C@@H](c1ccc(OCc2ccc(C)c(Cl)c2)cc1)CO3
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1S(=O)(=O)c1sc(N(CC2CCCC2)C(C)=O)nc1C)O[C@@H](c1ccc(OCc2ccc(C)c(Cl)c2)cc1)CO3

Procedure:
(S)-2-({(S)-7-(2-Acetylamino-4-methyl-thiazole-5-sulfonyl)-3-[4-(3-chloro-4-methyl-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]-dioxino-[2,3-g]isoquinoline-8-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester (24 mg) was reacted with iodomethyl cyclopentane (11 mg) according to General Procedure T to obtain (S)-2-({(S)-7-[2-(Acetyl-cyclopentylmethyl-amino)-4-methyl-thiazole-5-sulfonyl]-3-[4-(3-chloro-4-methyl-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester. This was hydrolyzed according to General Procedures N and B to give the title compound. LCMS: (m/z) 972.
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN(C)CCN(C)C.C([Li])(CC)C.[O:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[CH:31]=[O:32]>C(OCC)C>[O:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[CH:31]([CH:12]1[CH2:11][CH2:10][CH2:9][N:8]1[C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[OH:32]
Reactant: CC(C)(C)OC(=O)N1CCCC1
Reactant: O=Cc1ccco1
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCCC1C(O)c1ccco1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
N-Boc-pyrrolidine (5.0 g) is dissolved in diethyl ether (60 mL) and the solution is cooled to −78° C. N,N,N′,N′-Tetramethylethylenediamine (TMEDA) (4.4 mL) is added to the mixture followed by sec-butyl lithium (27.0 mL, 1.3 M in cyclohexane) maintaining the temperature below −60° C. After 2 h, 2-furaldehyde (2.9 mL) is added and the mixture is stirred at −70° C. for an additional 30 min. The reaction mixture is allowed to warm to room temperature and is then quenched with water (25 mL) and poured into EtOAc (200 mL). The separated organic layer is washed with saturated aq. ammonium chloride (3×50 mL) followed by brine (50 mL), dried (MgSO4), and concentrated The crude product is purified by column chromatography (heptane/EtOAc, 8/1; 5/1) to afford 4.97 g of 2-furyl(N-Boc-pyrrolidin-2-yl)methanol as a mixture of diastereomers. The resulting 2-furyl(N-Boc-pyrrolidin-2-yl)methanol (4.43 g) is dissolved in dichloromethane (200 mL) and trifluoroacetic acid (30 mL) is added. The mixture is poured into a 1 M solution of sodium hydroxide. The organic layer is separated and washed with saturated aq. sodium bicarbonate (2×100 mL). The aqueous layers are extracted with dichloromethane (4×50 mL) and the combined organic layers are concentrated. The crude product is purified by column chromatography (CH2Cl2/methanol/NH4OH, 95/5/1; 90/10/1). The resulting oil is distilled in a Kugelrohr apparatus (0.175-200° C., 0.2 Torr) to afford 0.20 g of the title compound as a mixture of diastereomers. Physical characteristics. MS (ESI+) m/z 168 (M+H)+.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[CH2:18][NH:19][C:20]([NH:22][CH2:23][C:24]([NH:26][NH2:27])=[O:25])=[O:21]>C(O)(=O)C>[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[CH2:18][NH:19][C:20]([NH:22][CH2:23][C:24]([NH:26][N:27]=[C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([I:1])[CH:3]=2)[NH:7][C:6]1=[O:11])=[O:25])=[O:21]
Reactant: O=C1Nc2ccc(I)cc2C1=O
Reactant: NNC(=O)CNC(=O)NCc1ccco1
Solvent: CC(=O)O
Product: O=C(CNC(=O)NCc1ccco1)NN=C1C(=O)Nc2ccc(I)cc21
Temperature: 100 °C
Yield: 71 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added N-(2-furylmethyl)-N′-(2-hydrazino-2-oxoethyl)urea. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 71 mg of the title compound (71%) as a yellow solid in 95.6% purity by HPLC (Rt: 4.26, gradient of 10 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: Br[C:2]1[C:3]([N:5]([CH3:10])[C:6](=[O:9])[C:7]=1[Br:8])=[O:4].C([O-])([O-])=O.[Cs+].[Cs+].[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>CN(C=O)C>[Br:8][C:7]1[C:6](=[O:9])[N:5]([CH3:10])[C:3](=[O:4])[C:2]=1[N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1
Reactant: C1COCCN1
Reactant: CN1C(=O)C(Br)=C(Br)C1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CN1C(=O)C(Br)=C(N2CCOCC2)C1=O
Reaction time: 0.5 h
Yield: 79.1 %

Procedure:
To a room temperature, stirred solution of 2,3-dibromo-N-methylmaleimide (1 g, 0.004 mol) in DMF (10 mL) was added Cs2CO3(1.34 g, 0.004 mol) followed by morpholine (360 mg, 0.004 mol) under N2 atmosphere. The reaction mixture was then stirred for 30 minutes, quenched with ice water, and extracted with EtOAc (2×50 mL). The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford 3-bromo-1-methyl-4-morpholino-1H-pyrrole-2,5-dione (0.87 g, 85%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20]Cl)=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[CH3:26][NH:27][CH:28]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:29][OH:30].C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[CH2:31]([CH:28]([N:27]([CH2:20][C:18]1[S:19][C:12]2[C:11](=[O:23])[C:10]([C:8]([NH:7][CH2:6][C:5]3[CH:24]=[CH:25][C:2]([Cl:1])=[CH:3][CH:4]=3)=[O:9])=[CH:15][N:14]([CH3:16])[C:13]=2[C:17]=1[CH3:22])[CH3:26])[CH2:29][OH:30])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CNC(CO)Cc1ccccc1
Reactant: Cc1c(CCl)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(CN(C)C(CO)Cc2ccccc2)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Temperature: 60 °C
Reaction time: 10 h
Yield: 76.3 %

Procedure:
A mixture of N-(4-chlorobenzyl)-2-(chloromethyl)-3,4-dimethyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide (50 mg, 0.13 mmol), 2-(methylamino)-3-phenylpropan-1-ol (Tetrahedron 2001, 57, 3425)(33 mg, 0.20 mmol) and diisopropylethylamine (35 μL, 0.20 mmol) in dry DMF (2.7 mL) was heated to 60° C., becoming a solution. The reaction was stirred for 10 hours at that temperature. After cooling to room temperature, the solution was diluted with water (7 mL). The resulting milky suspension was stirred vigorously for 30 minutes, and then left standing overnight at room temp. The mixture was filtered, and the collected solid was washed with water and dried in vacuo, leaving a white solid. Recrystallization from acetonitrile (5 mL, dissolved with warming and then cooled to 0° C. overnight) gave the title compound (52 mg) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH:16]=[C:17]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[CH:18]=[CH:19][C:12]2=[N:11][C:10]=1[C:26](O)=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:30][CH2:31][C:32](=[O:41])[CH2:33][C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=1>>[Cl:40][C:37]1[CH:36]=[CH:35][C:34]([CH2:33][C:32](=[O:41])[CH2:31][NH:30][C:26]([C:10]2[N:11]=[C:12]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:21][CH2:22][O:23][CH2:24][CH2:25]4)=[CH:16][N:13]3[C:14](=[O:15])[C:9]=2[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:27])=[CH:39][CH:38]=1
Reactant: NCC(=O)Cc1ccc(Cl)cc1
Reactant: O=C(O)c1nc2ccc(N3CCOCC3)cn2c(=O)c1OCc1ccccc1
Agent: Cl
Product: O=C(CNC(=O)c1nc2ccc(N3CCOCC3)cn2c(=O)c1OCc1ccccc1)Cc1ccc(Cl)cc1

Procedure:
Adapted the procedure of example 2 using 3-benzyloxy-7-morpholin-4-yl-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxylic acid and 1-amino-3-(4-chloro-phenyl)-propan-2-one hydrochloride (AU2007001980) as starting material
Reaction SMILES: [N:1]([CH:4]1[CH2:27][C:8]2=[CH:9][N:10]([S:17]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[C:11]3[CH:12]=[CH:13][C:14]([O:15][CH3:16])=[C:6]([C:7]=32)[C:5]1=[O:28])=[N+]=[N-].C(O)C.[ClH:32]>[C].[Pd]>[ClH:32].[NH2:1][CH:4]1[CH2:27][C:8]2=[CH:9][N:10]([S:17]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[C:11]3[CH:12]=[CH:13][C:14]([O:15][CH3:16])=[C:6]([C:7]=32)[C:5]1=[O:28]
Reactant: COc1ccc2c3c(cn2S(=O)(=O)c2ccc(C)cc2)CC(N=[N+]=[N-])C(=O)c13
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: COc1ccc2c3c(cn2S(=O)(=O)c2ccc(C)cc2)CC(N)C(=O)c13
Temperature: 25 °C
Reaction time: 4 h
Yield: 80 %

Procedure:
To a suspension of 4-azido-3,4-dihydro-6-methoxy-1-p-toluenesulfonylbenz[cd]indol-5(1H)-one (2.0 g, 5.0 mmol) in ethanol (100 mmol) were added conc. hydrochloric acid (2.5 ml) and 10% palladium-carbon (400 mg). The mixture was stirred for 4 hours at room temperature under hydrogen atmosphere of 3 atmospheres pressure. After completion of the reaction, the catalyst was filtered off. The filtrate was subjected to distillation, and the residue was washed with ethyl ether to give 1.6 g (80%) of crude crystals of the title compound.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:4]([CH:18]([NH:20]C(=O)OC(C)(C)C)[CH3:19])[O:3]1.[ClH:28].O1CCOCC1>C(Cl)Cl>[ClH:28].[NH2:20][CH:18]([C:4]1[O:3][C:2](=[O:1])[C:11]2[C:6]([C:5]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH3:19]
Reactant: CC(NC(=O)OC(C)(C)C)c1oc(=O)c2ccccc2c1-c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(N)c1oc(=O)c2ccccc2c1-c1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
tert-butyl 1-(1-oxo-4-phenyl-1H-isochromen-3-yl)ethylcarbamate (Intermediate E1, 112 mg, 0.306 mmol) was dissolved in DCM (3 ml), then a solution of 4M HCl in dioxane (3 ml, 12.00 mmol) was added and the mixture stirred rt for 4 h. The reaction was quenched by the addition of Et2O (50 mL) and the mixture dried under reduced pressure to afford the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[CH2:19][N:20]2[CH:24]=[CH:23][N:22]=[CH:21]2)=[CH:9]\[C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13](O)=[O:14])=[CH:4][CH:3]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH3:39][O:40][C:41](=[O:49])[C@:42]([CH3:48])([CH2:44][CH2:45][S:46][CH3:47])[NH2:43].CN1CCOCC1>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[CH2:19][N:20]2[CH:24]=[CH:23][N:22]=[CH:21]2)=[CH:9]\[C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([NH:43][C@@:42]([CH3:48])([CH2:44][CH2:45][S:46][CH3:47])[C:41]([O:40][CH3:39])=[O:49])=[O:14])=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@](C)(N)CCSC
Reactant: O=C(O)c1cccc(/C=C(/Cn2ccnc2)c2ccc(F)cc2)c1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(=O)[C@](C)(CCSC)NC(=O)c1cccc(/C=C(/Cn2ccnc2)c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 50 %

Procedure:
To a mixture of 3-((E)-2-(4-fluorophenyl)-3-(imidazol-1-yl)-prop-1-enyl)benzoic acid (0.50 g, 1.55 mmol; prepared as the product of step D in Example 1), EDC (0.30 g, 1.55 mmol) and HOBt (0.21 g, 1.55 mmol) in dichloromethane (20 ml) was added α-methyl methionine methyl ester (0.33 g, 1.55 mmol) and 4-methylmorpholine (0.17 ml, 1.55 mmol). The solution was stirred at room temperature for 17 hrs, washed with brine (3×40 ml) dried over (MgSO4) and the solvent evaporated to leave a yellow gum. This was purified by chromatography (Biotage flash 40, 40 g SiO2 cartridge) eluting a gradient of 0-1% 0.88 aqueous ammonia/EtOAc to give the desired end product as a yellow gum 0.38 g (50%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12](O)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH2:63]([N:67]([CH2:70][CH:71]1[CH2:76][CH2:75][CH2:74][CH2:73][NH:72]1)[CH2:68][CH3:69])[CH2:64][CH2:65][CH3:66]>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:72]1[CH2:73][CH2:74][CH2:75][CH2:76][CH:71]1[CH2:70][N:67]([CH2:63][CH2:64][CH2:65][CH3:66])[CH2:68][CH3:69])=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CCCCN(CC)CC1CCCCN1
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CCCCN(CC)CC1CCCCN1C(=O)c1cc2ncnc(NC(C)c3nc4cc(Cl)ccc4[nH]3)c2cc1Cl

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and N-butyl-N-ethyl-C-(piperidin-2-yl)-methylamine in DMSO at ambient temperature.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([I:11])=[C:9](Cl)[N:8]=[C:7]([Cl:13])[N:6]=1)=[O:4].[NH3:14]>CS(C)=O>[CH3:1][O:2][C:3]([C:5]1[C:10]([I:11])=[C:9]([NH2:14])[N:8]=[C:7]([Cl:13])[N:6]=1)=[O:4]
Reactant: COC(=O)c1nc(Cl)nc(Cl)c1I
Reactant: N
Solvent: CS(C)=O
Product: COC(=O)c1nc(Cl)nc(N)c1I
Reaction time: 1.5 h
Yield: 89 %

Procedure:
2,6-Dichloro-5-iodopyrimidine-4-carboxylic acid methyl ester (12 g, 36 mmol) was dissolved in dry dimethyl sulfoxide (DMSO; 100 mL) and treated with a stream of ammonia at such a rate when combined with external water bath cooling to keep the temperature in the range of 20-30° C. After 90 min, the ammonia addition was complete and excess ammonia was removed from the mixture by sparging with a stream of nitrogen for 20 min. The mixture was poured into water (200 mL) with stirring and the precipitated product was extracted with ethyl acetate (75 mL) twice. The combined ethyl acetate extracts were washed twice with water (50 mL), once with saturated NaCl solution, dried and evaporated to give the title compound (10 g, 89% yield) that was used without further purification. MS: M/Z=313.