Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1([CH:8]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]#[C:30][Si](C)(C)C)[CH:24]=2)[CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+]>CO>[C:29]([C:25]1[CH:24]=[C:23]([CH:8]([C:2]2([OH:1])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)[CH2:9][N:10]2[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH2:15]2)[CH:28]=[CH:27][CH:26]=1)#[CH:30]
Reactant: CC(C)(C)OC(=O)N1CCN(CC(c2cccc(C#C[Si](C)(C)C)c2)C2(O)CCCCC2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1cccc(C(CN2CCN(C(=O)OC(C)(C)C)CC2)C2(O)CCCCC2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.9 %

Procedure:
To a solution of tert-butyl 4-(2-(1-hydroxycyclohexyl)-2-{3-[(trimethylsilyl)ethynyl]phenyl}ethyl)piperazine-1-carboxylate (104 mg, 0.215 mmol) in methanol (3 mL) was added potassium carbonate (300 mg, 2.17 mmol) and the mixture was stirred for 30 min at room temperature. The reaction mixture was quenched with aqueous ammonium chloride (5 mL) and extracted with ethyl acetate. The organic layer was washed with water, brine, dried (sodium sulfate), filtered and concentrated to give a crude oil, which was purified via silica gel flash chromatography (gradient from 10% ethyl acetate/hexane to 30% ethyl acetate/hexane) to yield 70 mg (80%) tert-butyl 4-[2-(3-ethynylphenyl)-2-(1-hydroxycyclohexyl)ethyl]piperazine-1-carboxylate as a white solid. MS (ESI) m/z 413 ([M+H]+); HRMS: calcd for C25H36N2O3+H, 413.2804; found (ESI, [M+H]+), 413.2809.
Reaction SMILES: [CH3:1][C@H:2]1[C@H:15]([CH3:16])[C@@H:14]2[C@:5]3([CH2:19][CH2:18][NH:17][C@@H:13]2[CH2:12][C:11]2[CH:10]=[CH:9][C:8]([O:20][CH3:21])=[C:7]([OH:22])[C:6]3=2)[CH2:4][C:3]1=[O:23].C([O-])(O)=O.[Na+].[CH:29]1([CH2:32]Br)[CH2:31][CH2:30]1.[ClH:34]>CN(C=O)C.C(O)C>[ClH:34].[CH:29]1([CH2:32][N:17]2[CH2:18][CH2:19][C@@:5]34[C:6]5[C:7]([OH:22])=[C:8]([O:20][CH3:21])[CH:9]=[CH:10][C:11]=5[CH2:12][C@@H:13]2[C@@H:14]3[C@@H:15]([CH3:16])[C@H:2]([CH3:1])[C:3](=[O:23])[CH2:4]4)[CH2:31][CH2:30]1
Reactant: BrCC1CC1
Reactant: COc1ccc2c(c1O)[C@]13CCN[C@H](C2)[C@@H]1[C@@H](C)[C@H](C)C(=O)C3
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: COc1ccc2c(c1O)[C@]13CCN(CC4CC4)[C@H](C2)[C@@H]1[C@@H](C)[C@H](C)C(=O)C3
Yield: 90 %

Procedure:
A mixture of 18b (7.20 g, 22.8 mmole), NaHCO3 (3.84 g, 45.7 mmole) and cyclopropylmethyl bromide (3.70 g, 27.4 mmole) in DMF (100 ml) was heated at 100° under argon for 2.5 hours. The mixture was processed as described for 19a-CPM to give 8.31 g (99%) of 19b-CPM as a foam. NMR: δ 6.90 (aromatic); 6.35, broad s, 1H (hydroxyl proton); 4.23 (H-5α); 3.78 (CH3O--); 1.10, unsymmetrical d, (8β-CH3, J=5 Hz); 0.92 symmetrical d, (7α-CH3, J=6 Hz). The foam was converted to the HCl salt by dissolving the free base in ethanol, adding an excess of concentrated HCl followed by evaporation to dryness. The residue was azeotroped with 1:1 ethanol-toluene, then toluene and finally crystallized from acetone to give 8.24 g (90%) of 19b-CPM.HCl, mp 194°-195°. Recrystallization from acetone gave an analytical sample of 19b-CPM.HCl as the hemi-acetone solvate. The presence of acetone was confirmed by the nmr of 19b-CMP.HCl taken in DMSO-d6.
Reaction SMILES: Br[CH:2]([C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[CH:17][CH:16]=[CH:15]2)[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[N:6]=1)=O.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1.O>CN(C)C=O>[CH3:11][C:7]1[N:6]=[C:5]([C:3]2[N:22]=[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]3[C:2]=2[C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]=[CH:17][CH:16]=[CH:15]3)[CH:10]=[CH:9][CH:8]=1
Reactant: Nc1ccccn1
Reactant: Cc1cccc(C(=O)C(Br)c2ccc3ncccc3c2)n1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cccc(-c2nc3ccccn3c2-c2ccc3ncccc3c2)n1
Temperature: 80 °C
Yield: 24.8 %

Procedure:
A solution of 2-bromo-1-(6-methyl-pyridin-2-yl)-2-quinolin-6-yl-ethanone of Step D (60 mg, 0.176 mmol)in dimethylformamide (1 mL) was treated with 2-aminopyridine (50 mg, 0.53 mmol, 3 equiv), and heated to 80° C. over 4.5 hours. After cooling down, the mixture was treated with water and extracted with ethyl acetate. The organics were concentrated in vacuo and reverse phase column chromatography (a gradient from 5-30% acetonitrile in 0.1% aqueous formic acid) provided the title compound (14.7 mg, 25%). HPLC tR=1.71 min, LCMS 337.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12](O)=[O:13].C([O-])(=O)C.[NH4+:23]>>[Cl:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([NH2:23])=[O:13]
Reactant: [NH4+]
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1Cl
Agent: CC(=O)[O-]
Product: NC(=O)c1ccncc1Nc1ccc(I)cc1Cl

Procedure:
3-[(2-chloro-4-iodophenyl)amino]isonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 6 mmol of 3-[(2-chloro-4-iodophenyl)amino]isonicotinic acid (intermediate 2) and 12 mmol of. ammonium acetate. LC/MS [8.29 min; 374 (M+1)]
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][N:15]=1)[C:9]([O:11]C)=[O:10])(=[O:4])[CH2:2][CH3:3].[OH-].[Na+]>CO>[C:1]([NH:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][N:15]=1)[C:9]([OH:11])=[O:10])(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)Nc1cc(C(=O)OC)ccn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCC(=O)Nc1cc(C(=O)O)ccn1
Temperature: 50 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
A mixture of methyl 2-propionamidoisonicotinate (1.07 g, 5.15 mmol), 2M aqueous sodium hydroxide solution (5 mL) and methanol (25 mL) is stirred at 50° C. for 2 hours. After removal of the methanol by evaporation, the solution is acidified by 2M hydrochloric acid and extracted with ethyl acetate. The organic layer is dried over sodium sulfate and concentrated in vacuo. The residue is crystallized from tetrahydrofuran and n-hexane to give 0.76 g (76% yield) of the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[CH2:13][CH2:14][N:15]1[CH2:19][CH2:18][C@@H:17]([CH2:20][NH2:21])[CH2:16]1.C(N(C(C)C)CC)(C)C.[O:31]=[C:32]1[CH2:37][S:36][C:35]2[CH:38]=[CH:39][C:40]([C:42](O)=[O:43])=[N:41][C:34]=2[NH:33]1.O.OC1C2N=NNC=2C=CC=1.C(Cl)CCl>CN(C=O)C>[CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[CH2:13][CH2:14][N:15]1[CH2:19][CH2:18][C@@H:17]([CH2:20][NH:21][C:42]([C:40]2[CH:39]=[CH:38][C:35]3[S:36][CH2:37][C:32](=[O:31])[NH:33][C:34]=3[N:41]=2)=[O:43])[CH2:16]1
Reactant: O=C1CSc2ccc(C(=O)O)nc2N1
Reactant: COc1ccc2nccc(CCN3CC[C@@H](CN)C3)c2n1
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COc1ccc2nccc(CCN3CC[C@@H](CNC(=O)c4ccc5c(n4)NC(=O)CS5)C3)c2n1
Reaction time: 18 h
Yield: 72.5 %

Procedure:
To a stirred solution of [((3S)-1-{2-[6-(methyloxy)-1,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinyl)methyl]amine (0.14 g, 0.49 mmole) in dry in DMF (25 mL) at RT was added diisopropylethylamine (0.10 mL, 0.54 mmole), 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylic acid (0.10 g, 0.49 mmole), hydroxybenzotriazole hydrate (0.73 g, 0.54 mmole) and EDC (0.10 g, 0.54 mmole). After 18 h, the reaction contents were concentrated under high vacuum. Purification on silica (CHCl3/MeOH, 9:1 containing 5% NH4OH) afforded the title compound (0.17 g, 75%) as a light yellow solid: 1H NMR (400 MHz, CD3OD) δ 9.05 (m, 1H), 8.47 (d, J=9.2 Hz, 1H), 8.25 (m, 2H), 7.92 (m, 1H), 7.72 (m, 1H), 7.62 (d, J=9.2 Hz, 1H), 4.22 (s, 3H), 3.91 (m, 2H), 3.82 (m, 2H), 3.67 (s, 2H), 3.65 (m, 2H), 3.44 (m, 2H), 3.18 (m, 2H), 2.98 (m, 1H), 2.37 (m, 1H), 2.05 (m, 1H). LC-MS (ES) m/e 479 (M+H)+.
Reaction SMILES: [NH2:1][C@:2]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:34])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1.CN(C)CCC(N[C@]12CC[C@@H](C(C)=C)[C@@H]1[C@@H]1[C@@](C)(CC2)[C@@]2(C)[C@@H]([C@]3(C)[C@@H](CC2)C(C)(C)C(C2C=CC(C(O)=O)=CC=2)=CC3)CC1)=O.[N:87]1([CH2:96][C:97]([OH:99])=O)[C:95]2[C:90](=[CH:91][CH:92]=[CH:93][CH:94]=2)[CH:89]=[CH:88]1>>[N:87]1([CH2:96][C:97]([NH:1][C@:2]23[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]2[C@@H:4]2[C@@:17]([CH3:20])([CH2:18][CH2:19]3)[C@@:16]3([CH3:21])[C@@H:7]([C@:8]4([CH3:34])[C@@H:13]([CH2:14][CH2:15]3)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]3[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:32][CH:33]=3)=[CH:10][CH2:9]4)[CH2:6][CH2:5]2)=[O:99])[C:95]2[C:90](=[CH:91][CH:92]=[CH:93][CH:94]=2)[CH:89]=[CH:88]1
Reactant: O=C(O)Cn1ccc2ccccc21
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: C=C(C)[C@@H]1CC[C@]2(NC(=O)CCN(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(NC(=O)Cn3ccc4ccccc43)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 31 %

Procedure:
The title compound was prepared in 31% yield from methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate following the same procedure as described for the preparation of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(dimethylamino)propanamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid, except 2-(1H-indol-1-yl)acetic acid was used instead of 3-(dimethylamino)propionic acid hydrochloride in Step 1. LCMS: m/e 687.6 (M+H)+, 2.60 min (method 6). 1H NMR (400 MHz, 1:1 CDCl3:MeOD) δ=7.92 (d, J=8.5 Hz, 2H), 7.72 (d, J=7.8 Hz, 1H), 7.40-7.35 (m, 1H), 7.32-7.25 (m, 1H), 7.24-7.16 (m, 4H), 6.71 (dd, J=0.8, 3.3 Hz, 1H), 5.27 (dd, J=1.6, 6.1 Hz, 1H), 4.90 (s, 1H), 4.83 (s, 2H), 4.44 (s, 1H), 4.33 (d, J=1.8 Hz, 1H), 2.48 (d, J=12.5 Hz, 1H), 2.39-2.31 (m, 1H), 2.08 (dd, J=6.4, 17.2 Hz, 1H), 1.64 (d, J=16.6 Hz, 1H), 1.54 (d, J=8.0 Hz, 2H), 1.50 (s, 3H), 1.39 (br. s., 3H), 1.37-1.23 (m, 6H), 1.23-1.13 (m, 4H), 1.04 (br. s., 1H), 1.00 (s, 4H), 0.95 (s, 3H), 0.92 (s, 3H), 0.87 (s, 3H), 0.82 (s, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:3][CH:2]=1.CC(C)([O-])C.[K+].O1CCCC1.Br[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36]>CN(C)C=O>[CH2:20]([O:19][C:17]([C:9]1[N:10]([CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:11]2[C:16]([C:8]=1[NH:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:18])[CH3:21]
Reactant: CCOC(=O)CBr
Reactant: CCOC(=O)c1[nH]c2ccccc2c1Nc1ccncc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c(C(=O)OCC)c(Nc2ccncc2)c2ccccc21
Temperature: 0 °C
Yield: 50 %

Procedure:
Under nitrogen, stir and cool to 0° C. a mixture of ethyl 3-(4-pyridinylamino)indole-2-carboxylate (see U.S. Pat. No. 5,328,920; 0.20 g, 0.711 mmol) in dimethylformamide (5 mL). Add a 1M solution of potassium tert-butoxide in tetrahydrofuran (0.75 mL, 0.75 mmol) in one portion, stir for 10 min, and then add ethyl bromoacetate (0.12 g, 0.72 mmol) in one portion. Stir at 0° C. for 50 min and quench the reaction into water (30 mL). Extract the aqueous mixture with ethyl acetate (2×20 mL), combine the extracts, wash with water (25 mL), brine (25 mL) and dry over MgSO4. Concentrate under vacuum, chromatograph the residue on a Redisep silica gel cartridge (10 g) eluting with 5% methanol/dichloromethane to 20% methanol/dichloromethane. Combine non-homogeneous fractions concentrate and chromatograph again as above. Combine all homogenous fractions and concentrate to obtain 0.13 g (50%) of the title compound as a white solid: MS 368(M+H).
Reaction SMILES: [CH:1]([C:5]1[CH:6]=[CH:7][C:8]2[CH2:9][C:10]3[C:23]([C:24](=O)[C:25]=2[CH:26]=1)=[CH:22][C:21]1[CH2:20][C:19]2[C:14](=[CH:15][C:16]([CH:28]([CH2:30][CH3:31])[CH3:29])=[CH:17][CH:18]=2)[C:13](=O)[C:12]=1[CH:11]=3)([CH2:3][CH3:4])[CH3:2]>COCCOCCOC>[CH:1]([C:5]1[CH:6]=[CH:7][C:8]2[C:25](=[CH:24][C:23]3[C:10]([CH:9]=2)=[CH:11][C:12]2[C:21](=[CH:20][C:19]4[C:14]([CH:13]=2)=[CH:15][C:16]([CH:28]([CH2:30][CH3:31])[CH3:29])=[CH:17][CH:18]=4)[CH:22]=3)[CH:26]=1)([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)c1ccc2c(c1)C(=O)c1cc3c(cc1C2)C(=O)c1cc(C(C)CC)ccc1C3
Solvent: COCCOCCOC
Product: CCC(C)c1ccc2cc3cc4cc5cc(C(C)CC)ccc5cc4cc3cc2c1
Temperature: 60 °C
Reaction time: 5 h

Procedure:
A mixture of 2 grams of 3,10-di-sec-butyl-7,14-dihydropentacene-5,12-dione and 45.3 mL of 2-methoxyethyl ether was stirred and flushed with nitrogen for 15 minutes. To this was added 1.52 grams of sodium borohydride and the mixture was heated to 60° C. overnight. The mixture was cooled to room temperature. To the mixture was added 0.4 grams of sodium borohydride and stirring was continued for 30 mintues. To the mixture was added 15 mL of isopropyl alcohol and stirring was continued at room temperature for 5 hours. To the mixture was added 15 mL of methanol. To the mixture was added 1.0 grams of sodium borohydride and stirring was continued at room temperature. To the mixture was added 16 mL of acetic acid and the mixture was heated to 60° C. for one hour. To the mixture was added 16 mL of concentrated hydrochloric acid and heating was continued at 60° C. The resulting solid was collected by filtration and washed with water followed by ethyl acetate and then acetone. The solid was dried to give 2,9-di-sec-butylpentacene.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][OH:11])=[CH:7][CH:8]=2)[CH2:3][NH:2]1.C(N(CC)CC)C.Cl[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]>O1CCCC1>[CH2:23]([O:22][C:20]([N:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[C:6]([CH2:10][OH:11])[CH:5]=2)[CH2:1]1)=[O:21])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: OCc1ccc2c(c1)CNC2
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1Cc2ccc(CO)cc2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
A mixture of (2,3-dihydro-1H-isoindol-5-yl)-methanol (1.34 g, 9.0 mmol) in anhydrous tetrahydrofuran (50 ml) was warmed gently to aid dissolution and allowed to cool to room temperature. Triethylamine (1.5 ml, 10.8 mmol) was added and the stirred mixture was treated dropwise with benzyl chloroformate (1.35 ml, 9.5 mmol) and stirred at room temperature for 3 hours. The solvent was removed in vacuo and the residue partitioned between ethyl acetate (30 ml) and 2M hydrochloric acid (30 ml). The organic layer was washed with water (30 ml), separated and the solvent removed in vacuo to afford a pink oil that solidified upon standing. The solids were triturated with 10% ethyl acetate in hexane (10 ml), filtered, rinsed with heptane (10 ml) and sucked dry to afford the title compound (2.5 g, 98%) as a pale pink solid. 1H NMR (DMSO-d6) 7.45-7.21 (8H, m), 5.20 (1H, t), 5.17 (2H, s), 4.71 (2H, br s), 4.64 (2H, br s), 4.50 (2H, d). MS: [M+H]+ 284.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=2)[C:17]#[N:18])[N:8]=1)=O.[F:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1[NH:31]N>>[F:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1[N:31]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=3)[C:17]#[N:18])[N:8]=2)=[CH:4][CH:3]=[N:2]1
Reactant: NNc1cc(F)ccc1F
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(C#N)c2)ccc1=O
Product: N#Cc1cccc(-n2ccc(=O)c(-c3ccnn3-c3cc(F)ccc3F)n2)c1

Procedure:
The product was obtained starting from 3-[3-((E)-3-Dimethylamino-acryloyl)-4-oxo-4H-pyridazin-1-yl]-benzonitrile (A-19) and 2,5-difluoro-phenylhydrazine according to the method described for example 91. MS: M=376.2 (M+H)+
Reaction SMILES: [N:1]1([C:7]2[S:8][CH:9]=[C:10]([CH:12]=O)[N:11]=2)[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.[S:14]1[CH2:20][C:18](=[O:19])[N:17]([CH2:21][C:22]([OH:24])=[O:23])[C:15]1=[S:16].[Cl-].[NH4+].N>C(O)C>[N:1]1([C:7]2[S:8][CH:9]=[C:10]([CH:12]=[C:20]3[S:14][C:15](=[S:16])[N:17]([CH2:21][C:22]([OH:24])=[O:23])[C:18]3=[O:19])[N:11]=2)[CH2:2][CH2:3][S:4][CH2:5][CH2:6]1
Reactant: O=C(O)CN1C(=O)CSC1=S
Reactant: O=Cc1csc(N2CCSCC2)n1
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: O=C(O)CN1C(=O)C(=Cc2csc(N3CCSCC3)n2)SC1=S

Procedure:
The reaction described in Example 1 was repeated, but using 0.85 g of 2-(thiomorpholin-4-yl)thiazole-4-carbaldehyde, 0.76 g of rhodanine-3-acetic acid, 0.4 g of ammonium chloride, 0.4 ml of 28% v/v aqueous ammonia and 30 ml of ethanol, giving the title compound as yellow crystals.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([CH:21]([OH:24])[CH2:22][CH3:23])[C:5]2[CH2:10][O:9][CH2:8][N:7]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[CH3:19])[C:6]=2[N:20]=1.[CH3:25][N:26]=[C:27]=[O:28].CN(C1C=CC=CN=1)C>ClCCl>[CH3:1][C:2]1[N:3]=[C:4]([CH:21]([O:24][C:27](=[O:28])[NH:26][CH3:25])[CH2:22][CH3:23])[C:5]2[CH2:10][O:9][CH2:8][N:7]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[CH3:19])[C:6]=2[N:20]=1
Reactant: CN=C=O
Reactant: CCC(O)c1nc(C)nc2c1COCN2c1c(C)cc(C)cc1C
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: CCC(OC(=O)NC)c1nc(C)nc2c1COCN2c1c(C)cc(C)cc1C

Procedure:
A mixture of 1-[7-methyl-1-(2,4,6-trimethyl-phenyl)-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-5-yl]-propan-1-ol (50 mg), methyl isocyanate (0.25 ml), dimethylaminopyridine (37 mg) in dichloromethane (2 ml) was heated at reflux for 1 hr. The mixture was quenched with water and extracted with chloroform. The organic layer was separated, dried and concentrated to give a clear oil (70 mg). The oil was purified by silica gel thin layer chromatography plate using 40% ethyl acetate in hexane as solvent to give 36 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:25])[N:10]([C@H:13]2[C@H:17]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[CH2:16][NH:15][CH2:14]2)[CH2:11][CH3:12])=[CH:4][CH:3]=1.[F:26][C:27]([F:44])([F:43])[C:28]1[CH:29]=[CH:30][C:31]([N:34]2[CH2:39][CH2:38][CH:37]([C:40](O)=[O:41])[CH2:36][CH2:35]2)=[N:32][CH:33]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:25])[N:10]([C@H:13]2[C@H:17]([C:18]3[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=3)[CH2:16][N:15]([C:40]([CH:37]3[CH2:38][CH2:39][N:34]([C:31]4[CH:30]=[CH:29][C:28]([C:27]([F:44])([F:26])[F:43])=[CH:33][N:32]=4)[CH2:35][CH2:36]3)=[O:41])[CH2:14]2)[CH2:11][CH3:12])=[CH:4][CH:3]=1
Reactant: O=C(O)C1CCN(c2ccc(C(F)(F)F)cn2)CC1
Reactant: CCN(C(=O)Oc1ccc(F)cc1)[C@@H]1CNC[C@H]1c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCN(c3ccc(C(F)(F)F)cn3)CC2)C[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.2 %

Procedure:
A mixture of 125 mg (0.456 mmol) rac-[(3S,4R)-4-(4-Chloro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl ester, 198 mg (0.547 mmol) 1-(5-(trifluoromethyl)pyridin-2-yl)piperidine-4-carboxylic acid, 208 mg (0.547 mmol) HATU and 353 mg (2.73 mmol) DIPEA in 10 mL DMF and stirred for 1 h ar room temperature. The mixture was concentrated and DMF and DIPEA was added and subjected to purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and NEt3. The product containing fractions were evaporated to yield 187 mg (66%) of the title compound as light brown viscous oil. MS m/e: 619.4 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:9](=[O:10])[CH:8]([C:11]([O:13]CC)=O)[C:6](=[O:7])[N:5]([CH3:16])[C:3]1=[O:4].[OH:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][C:19]=1[O:25][CH3:26].C(O)C>C1(C)C=CC=CC=1>[CH3:16][N:5]1[C:6](=[O:7])[CH:8]([C:11](=[O:13])[NH:22][C:21]2[CH:23]=[CH:24][C:18]([OH:17])=[C:19]([O:25][CH3:26])[CH:20]=2)[C:9](=[O:10])[N:2]([CH3:1])[C:3]1=[O:4]
Reactant: COc1cc(N)ccc1O
Reactant: CCOC(=O)C1C(=O)N(C)C(=O)N(C)C1=O
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc(NC(=O)C2C(=O)N(C)C(=O)N(C)C2=O)ccc1O
Temperature: 25 °C

Procedure:
6.85 g of 1,3-dimethyl-5-ethoxycarbonylbarbituric acid and 4.2 g of 4-hydroxy-3-methoxyaniline are suspended in 60 ml of toluene, and the suspension is heated under reflux for 3 hours, whereupon ethanol escapes. On cooling to room temperature a precipitate forms which is isolated by filtration, washed with ethanol and dried. Yield: 8.3 g (86% of theory). Melting point: 252°-253° C.
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[N:25]=[CH:26][N:27]([CH2:29][CH:30](OCC)[O:31]CC)[CH:28]=5)[S:23][C:16]=34)=[C:10]([F:37])[CH:9]=2)=[O:6])[CH2:3][CH2:2]1.Cl>CC(O)=O.O>[CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[N:25]=[CH:26][N:27]([CH2:29][CH:30]=[O:31])[CH:28]=5)[S:23][C:16]=34)=[C:10]([F:37])[CH:9]=2)=[O:6])[CH2:2][CH2:3]1
Reactant: CCOC(Cn1cnc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)c1)OCC
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: O=CCn1cnc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)c1
Temperature: 90 °C
Yield: 47.4 %

Procedure:
To a solution of acetal 263 (2.95 g, 5.61 mmol) in AcOH/H2O (20/20 mL) was added concentrated HCl (2 mL) and the reaction mixture was heated at 90° C. for 1 h. The reaction mixture was concentrated, diluted with water and 4M NaOH to pH 10 to form a precipitate that was collected by filtration, washed with water and dried under vacuum. The material was then purified by Biotage (SNAP 100 g cartridge; 2% of ammonium hydroxide in MeOH/DCM: 0/100 to 15/85, over 20 CV) to afford the title compound 264 (1.2 g, 2.66 mmol, 47% yield) as a brown solid. MS (m/z): 484.51 (M+H).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:10]=[C:11]=[O:12])[CH3:9].[CH3:13][C:14]1[NH:18][N:17]=[C:16]([O:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[C:22]([CH3:29])[CH:21]=2)[CH:15]=1.Cl>C(OCC)(=O)C>[CH2:8]([NH:10][C:11]([N:18]1[C:14]([CH3:13])=[CH:15][C:16]([O:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[C:22]([CH3:29])[CH:21]=2)=[N:17]1)=[O:12])[CH3:9]
Reactant: CCN=C=O
Reactant: Cc1cc(Oc2ccc([N+](=O)[O-])c(C)c2)n[nH]1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCNC(=O)n1nc(Oc2ccc([N+](=O)[O-])c(C)c2)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.2 %

Procedure:
Triethylamine (0.18 g, 1.8 mmol) and ethyl isocyanate (0.13 g, 1.8 mmol) were added to a solution of 5-methyl-3-(3-methyl-4-nitrophenyloxy)pyrazole (0.35 g, 1.5 mmol) in ethyl acetate (10 ml), and the mixture was stirred at room temperature for 8 hours. After completion of the reaction, the reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate (10 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/7), to give a white solid of N-ethyl-5-methyl-3-(3-methyl-4-nitrophenyloxy)pyrazole-1-carboxamide (0.27 g, yield: 59.2%). mp: 67-69° C.; 1H-NMR (CDCl3, TMS, ppm): δ 1.24 (t, J=7.3 Hz, 3H), 2.63 (s, 6H), 3.40 (dq, J=5.9 and 7.3 Hz, 2H), 5.79 (q, J=0.8 Hz, 1H), 6.85-7.00 (m, 1H), 7.00-7.15 (m, 2H), 8.07 (d, J=8.6 Hz, 1H).