Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14].C(N(CC)CC)C.[N+:29]([C:32]1[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][CH:33]=1)([O-:31])=[O:30]>CC(C)=O>[C:13]([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]([O:1][C:36](=[O:37])[C:35]1[CH:34]=[CH:33][C:32]([N+:29]([O-:31])=[O:30])=[CH:40][CH:39]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])([OH:15])=[O:14]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CCCCCCC(O)CCCCCCCCCCC(=O)O
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CCCCCCC(CCCCCCCCCCC(=O)O)OC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To a mixture of 12-Hydroxy stearic acid (450 grams, 1.5 moles), Triethylamine (313 ml, 2.35 moles) in Acetone (1 L) at 10-15° C., was added 4-Nitro Benzoyl Chloride (332 grams, 1.78 moles) and later stirred at room temperature for 10 hours. 75% of the solvent was distilled off. The resulting solution was cooled to room temperature and poured onto cold water. The pH of the solution was adjusted to 4-5 with dilute HCl, and resulting solid was filtered off and washed with chilled water. The solid was converted into slurry with 500 ml diisopropyl ether. The DIPE was filtered off and the resulting solid was dried in vacuum oven at 70-75° C. to yield pure 4-nitrobenzoic acid 11-carboxy-1-hexyl-undecyl ester product as white powder with a melting point of 98-101° C. The resulting compound was characterized by 1H NMR (DMSO-d6) δ 0.85 (t, 3H, CH3), 1.2-1.6 (m, 28H, 14×CH2), 1.8 (m, 2H, CH2), 2.32 (t, 2H, COCH2), 3.2 (m, 1H, CH) 8.1-8.25 (m, 4H, Ar).
Reaction SMILES: [C:1]1([C:13]2[C:14](=[O:28])[NH:15][C:16](=[O:27])[C:17]=2[C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][CH:19]=2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1.[H][H]>[Pd].CO>[C:1]1([C@H:13]2[C@@H:17]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[NH:20][CH:19]=3)[C:16](=[O:27])[NH:15][C:14]2=[O:28])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1
Reactant: O=C1NC(=O)C(c2cn3c4c(cccc24)CCC3)=C1c1c[nH]c2ccccc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O=C1NC(=O)[C@@H](c2cn3c4c(cccc24)CCC3)[C@H]1c1c[nH]c2ccccc12
Yield: 57.1 %

Procedure:
A suspension of 3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4(1H-indol-3-yl)pyrrole-2,5-dione (16 g, 43.6 mmol) and 10% palladium on carbon (Pd/C, wet catalyst) (8 g) were stirred under 1 atmosphere of hydrogen in methanol (600 ml) at room temperature for 48 hours. The catalyst was then filtered through a bed of Celite and the filtrate evaporated to dryness. The residue was re-dissolved in methanol and the product precipitated by the addition of cold water. The precipitate was filtered, washed with water and dried under vacuum to yield (±)-cis-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4(1H-indol-3-yl)pyrrolidine-2,5-dione (9.2 g). 1H NMR (DMSO-d6) 400 MHz δ: 11.56 (s, 1H), 10.66 (s, 1H), 7.43 (d, 1H, J=7.6 Hz), 7.14 (d, 2H, J=8 Hz), 6.86-6.97 (m, 4H), 6.78 (t, 1H, J=7.2 Hz), 6.69 (d, 1H, J=6.8 Hz), 4.88 (dd, 2H, J=9.2 and 45.6 Hz), 3.88 (m, 2H), 2.76 (t, 2H, J=5.6 Hz), 1.94 (t, 2H, J=6 Hz).
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].C([N:7](CC)CC)C.N[C:13]1[CH:14]=[C:15]([CH:24]=[CH:25][CH:26]=1)[NH:16][C:17](=[O:23])/[CH:18]=[C:19](\[O:21][CH3:22])/[CH3:20]>O1CCCC1>[CH3:1][N:2]([C:13]1[CH:14]=[C:15]([CH:24]=[CH:25][CH:26]=1)[NH:16][C:17](=[O:23])/[CH:18]=[C:19](\[O:21][CH3:22])/[CH3:20])[C:3]([NH2:7])=[O:4]
Reactant: CO/C(C)=C\C(=O)Nc1cccc(N)c1
Reactant: CN=C=O
Reactant: CCN(CC)CC
Solvent: C1CCOC1
Product: CO/C(C)=C\C(=O)Nc1cccc(N(C)C(N)=O)c1
Reaction time: 16 h

Procedure:
26 ml of methyl isocyanate were added to a mixture of 11.6 g of triethylamine and 22.3 g of m-amino-3-methoxy-crotonanilide in 250 ml of tetrahydrofuran and the mixture was stirred for 16 hours and vacuum filtered. The recovered precipitate was washed with isopropyl ether to obtain 23 g of m-(N-methyl-ureido)-3-methoxy-crotonanilide melting at 166° C. Crystallization from ethanol did not change the melting point.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[CH:4]=[O:5].I[CH2:12][CH3:13].C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O.O.CCOC(C)=O>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH2:12][CH3:13])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: CCI
Reactant: O=Cc1cc(O)ccc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOc1ccc(Br)c(C=O)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98.2 %

Procedure:
2-Bromo-5-hydroxybenzaldehyde (0.96 g, 4.8 mmol) was dissolved in anhydrous DMSO (10 mL). Iodoethane (0.50 mL, 6.2 mmol) and Cs2CO3 (1.9 g, 6.3 mmol) were added and the mixture stirred at room temperature for 1.5 hours. Additional Cs2CO3 (1.45 g, 4.8 mmol) was added to the reaction mixture and then was stirred for 30 minutes. The reaction mixture was diluted with H2O and EtOAc and the layers were separated. Brine was added to the aqueous layer and it was extracted twice with EtOAc. The combined organics were washed with 1M NaOH twice and brine thrice, and then was dried over MgSO4. The solution was vacuum-filtered through Celite® and concentrated in vacuo to give 1.08 g of 2-bromo-5-ethoxybenzaldehyde. 2-Bromo-5-ethoxy-benzaldehyde (1.02 g, 4.45 mmol) was dissolved in anhydrous toluene (10 mL) under N2. Diethyl phosphite (0.57 mL, 4.4 mmol), then MgO (0.45 g, 11.2 mmol) was added and the N2 inlet was removed. The mixture was stirred at room temperature for 1.75 hours, and more diethyl phosphite (0.1 mL, 0.77 mmol) was then added. The mixture was stirred for an additional 2.75 hours, then diluted with EtOAc, H2O, and saturated aqueous NaHCO3. The layers were separated and the organic layer was washed with brine, dried over MgSO4, vacuum-filtered through Celite® and conc in vacuo to give 1.70 g of crude material. The product was used without purification. Diethyl(2-bromo-5-ethoxyphenyl)-(hydroxy)-methyl-phosphonate (1.13 g, 3.08 mmol) was dissolved in anhydrous dichloromethane (13 mL). Pyridinium chlorochromate (1.22 g, 4.6 mmol) was added and the mixture was stirred at room temperature for 17 hours at which time additional pyridinium chlorochromate (1.1 g, 5.1 mmol) was added. The mixture was stirred at room temperature for 3 hours, and then was refluxed for 45 minutes under a drying tube. The reaction was diluted with dichloromethane and washed with H2O and saturated aq. NaHCO3, dried over MgSO4, vacuum-filtered through Celite® and concentrated in vacuo. The product was chromatographed (EtOAc-hexanes) to give diethyl(2-bromo-5-ethoxyphenyl)-oxomethylphosphonate. The diethyl (2-bromo-5-ethoxyphenyl)oxo-methyl-phosphonate was reacted with DAST according to Example 80C to give diethyl (2-bromo-5-ethoxyphenyl)difluoromethylphosphonate. Compound 93 was synthesized according to procedures similar to those of Example 40 from this corresponding diethyl phosphonate. MS (ES-): m/z 329.0, 331.0 (M−H). 1H NMR: (DMSO-d6, 400 MHz) δ 7.56 (d, J=8.8, 1H), 7.11 (d, J=2.7, 1H), 6.97 (dd, J=2.7, 8.8, 1H), 4.01 (q, J=7.2, 2H), 1.30 (t, J=7.2, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:13][C:14]#[CH:15])[C:10](O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:16][C:17]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:18]=1[C:19]([OH:21])=O.P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1.[C:49]1([NH:55][NH2:56])[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>N1C=CC=CC=1>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([C:10]1[N:56]([NH:55][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:19](=[O:21])[C:18]2[C:17](=[CH:25][C:24]([Cl:26])=[CH:23][CH:22]=2)[N:16]=1)[CH2:13][C:14]#[CH:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#CC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: NNc1ccccc1
Reactant: Nc1cc(Cl)ccc1C(=O)O
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: c1ccncc1
Product: C#CC[C@@H](NC(=O)OC(C)(C)C)c1nc2cc(Cl)ccc2c(=O)n1Nc1ccccc1
Temperature: 55 °C
Reaction time: 8 h
Yield: 53.3 %

Procedure:
To a mixture of (R)-2-tert-butoxycarbonylamino-pent-4-ynoic acid (5.0 g, 23.5 mmol) in anhydrous pyridine (20 ml) were added 2-amino-4-chloro-benzoic acid (4.03 g, 23.5 mmol) and triphenyl phosphite (7.40 ml). The reaction mixture was then heated at 55° C. for 16 h. To this was added phenylhydrazine (2.8 ml, 28.2 mmol). The resulting mixture was stirred at 100° C. for 8 h. After the solvent was removed, the residue was purified by flash column (hexane to 20% ethyl acetate in hexane) to give [(R)-1-(7-chloro-4-oxo-3-phenylamino-3,4-dihydro-quinazolin-2-yl)-but-3-ynyl]-carbamic acid tert-butyl ester (5.5 g, 53.4%) as off-white solid. M.p. 155-157° C. [LCMS]: 439 [M+H]. 400 MHz 1H NMR: (DMSO-d6) δ 9.21 and 9.0 (s, s, 1H, rotomers), 8.08 (m, 1H), 7.81 (m, 1H), 7.60 (dd, J=2.0, 6.4 Hz, 1H), 7.31-7.18 (m, 3H), 6.89-6.67 (m, 3H), 5.14-4.97 (m, br, 1H), 2.86 (m, br, 2H), 2.25 (m, 1H), 1.32 (s, 9H).
Reaction SMILES: [CH2:1]([Sn:5](Cl)(Cl)[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[F-:12].[F-:13].[NH4+].[NH4+]>>[CH2:1]([Sn:5]([F:13])([F:12])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4]
Reactant: [F-]
Reactant: CCCC[Sn](Cl)(Cl)CCCC
Agent: [NH4+]
Product: CCCC[Sn](F)(F)CCCC

Procedure:
reacting dibutyl tin chloride and ammonium difluoride to form dibutyl tin difluoride;
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH2:7][CH2:8][C:9]#[N:10].[Br:11]Br.O>C(O)(=O)C>[Br:11][C:4]1[S:3][C:2]([CH3:1])=[C:6]([CH2:7][CH2:8][C:9]#[N:10])[CH:5]=1
Reactant: Cc1sccc1CCC#N
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: Cc1sc(Br)cc1CCC#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.3 %

Procedure:
A solution of 3-(2-methylthiophen-3-yl)-propionitrile 60 (320 mg, 2.1 mmol) in acetic acid (5 mL) was treated with bromine (0.12 mL, 2.3 mmol) and the mixture stirred at rt for 1 hour. Water was added and the mixture was extracted with EtOAc (2×20 mL). The combined organics were washed with water and dried over MgSO4. Removal of the solvent followed with silica gel column chromatography (eluent: DCM/hexane, 1/1) gave 61 as a colorless liquid (330 mg). 1H NMR (400 MHz, CDCl3) δ: 2.35 (s, 3H), 2.53 (t, J=10.5 Hz, 2H), 2.84 (t, J=10.5 Hz, 2H) 6.80 (s, 1H).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.Cl.[OH:22][C@@H:23]1[CH2:27][NH:26][C@H:25]([C:28]([NH2:30])=[O:29])[CH2:24]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:26]3[CH2:27][C@@H:23]([OH:22])[CH2:24][C@H:25]3[C:28]([NH2:30])=[O:29])=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: NC(=O)[C@@H]1C[C@H](O)CN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)[C@@H]1C[C@H](O)CN1C(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with (2S,4S)-4-hydroxypyrrolidine-2-carboxamide hydrochloride (851233-67-5) in the presence of TBTU and DIEA to obtain the title compound as colorless oil; MS (EI): m/e=397.5 [MH+].
Reaction SMILES: C([O:3][C:4](=[O:33])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]3[CH:23]=[C:22]4[C:17]([C:18]([C:26]5[S:27][C:28]([CH3:31])=[CH:29][CH:30]=5)=[CH:19][C:20]([CH3:25])([CH3:24])[O:21]4)=[CH:16][C:15]=3[CH:32]=2)=[CH:7][CH:6]=1)C.[Li+].[OH-]>CO.C1COCC1.O>[CH3:24][C:20]1([CH3:25])[CH:19]=[C:18]([C:26]2[S:27][C:28]([CH3:31])=[CH:29][CH:30]=2)[C:17]2[C:22](=[CH:23][C:14]3[CH:13]=[CH:12][C:11]([C:8]4[CH:9]=[CH:10][C:5]([C:4]([OH:33])=[O:3])=[CH:6][CH:7]=4)=[CH:32][C:15]=3[CH:16]=2)[O:21]1
Reactant: CCOC(=O)c1ccc(-c2ccc3cc4c(cc3c2)C(c2ccc(C)s2)=CC(C)(C)O4)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(C2=CC(C)(C)Oc3cc4ccc(-c5ccc(C(=O)O)cc5)cc4cc32)s1
Reaction time: 20 h

Procedure:
To a solution of ethyl-4-[2,2-dimethyl-4-(5-methyl-thien-2-yl)-benzo[1,2-g]-chrom-3-en-7-yl]benzoate (Compound 11, 18 mg, 0.03 mmol) in methanol (0.5 mL) and THF (1 mL), was added LiOH in water (1M solution, 0.3 mL). The reaction mixture was stirred for 20 hours, the solvent was removed under reduced pressure, the residue dissolved in water (5 mL), washed with ether (10 ml) and the aqueous layer was acidified to PH 5. The aqueous layer was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine, dried, and the solvent was removed under reduced pressure to afford the title compound as a pale yellow solid.
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[CH3:6][C:7]1[S:15][C:10]2[N:11]=[CH:12][N:13]=[CH:14][C:9]=2[CH:8]=1.C[N:17]([CH3:24])[C:18]1[CH:23]=[CH:22][CH:21]=CC=1>>[Cl:3][C:14]1[C:9]2[CH:8]=[C:7]([CH3:6])[S:15][C:10]=2[N:11]=[C:12]([C:21]2[CH:24]=[N:17][CH:18]=[CH:23][CH:22]=2)[N:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc2cncnc2s1
Reactant: CN(C)c1ccccc1
Product: Cc1cc2c(Cl)nc(-c3cccnc3)nc2s1

Procedure:
The replacement of the keto group by Cl under the formation of the aromatic pyrimidine ring takes place under standard conditions. A mixture of POCl3 (18 ml) with 3,4-dihydro-4-oxo-2,4pyridin-3-yl)-6-methyl-thieno-[2,3-d]-pyrimidine (6 g) is refluxed for 4 hours under the addition of N,N-dimethylaniline (1,8 m). The usual workup yields 4-chloro-2-(pyridin-3-yl)-6-methyl-thieno-[2,3-d]-pyrimidine (5 g).
Reaction SMILES: C([O:4][C:5]1[CH2:8][C:7](=[O:9])[CH:6]=1)(=O)C.[CH:10]1([NH:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>C(OCC)(=O)C>[CH:17]1([NH2+:16][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]2)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1.[OH:9][C:7]1[CH2:8][C:5](=[O:4])[CH:6]=1
Reactant: C1CCC(NC2CCCCC2)CC1
Reactant: CC(=O)OC1=CC(=O)C1
Solvent: CCOC(C)=O
Product: C1CCC([NH2+]C2CCCCC2)CC1
Product: O=C1C=C(O)C1
Reaction time: 1.5 h
Yield: 111.8 %

Procedure:
1000 g of distillation residue from diketene production, containing 22.0 percent of 3-acetoxy-2-cyclobuten-1-one (1.74 mol), was dissolved in 1078 ml of ethyl acetate (970 g). 707.4 g of dicyclohexylamine (98 percent; 3.8I mol) was instilled in this black solution at 10° C. within 60 minutes. After 90 minutes, of stirring at +10° C., the suspension was filtered, suspended three times with ethyl acetate and dried under vacuum. 518 g of the title product with a content of 65.5 percent (HPLC), corresponding to a yield of 73.4 percent, relative to 3-acetoxy-2-cyclobuten-1-one, was obtained. Data for the title compound was:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[N:7]([CH2:11][C:12]#[CH:13])[C:6]=2[CH:14]=1.[C:15]1(=O)[O:20][C:18](=[O:19])[C:17]2[CH2:21][CH2:22][CH2:23][CH2:24][C:16]1=2.C(O)(=O)C>O>[CH2:11]([N:7]1[C:6]2[CH:14]=[C:2]([N:1]3[C:18](=[O:19])[C:17]4[CH2:21][CH2:22][CH2:23][CH2:24][C:16]=4[C:15]3=[O:20])[CH:3]=[CH:4][C:5]=2[O:9][C:8]1=[O:10])[C:12]#[CH:13]
Reactant: C#CCn1c(=O)oc2ccc(N)cc21
Reactant: O=C1OC(=O)C2=C1CCCC2
Solvent: O
Solvent: CC(=O)O
Product: C#CCn1c(=O)oc2ccc(N3C(=O)C4=C(CCCC4)C3=O)cc21
Temperature: 105 °C
Yield: 35 %

Procedure:
A mixture of 5-amino-3-(2-propynyl)-3H-benz-oxazol-2-one (0.50 g), 3,4,5,6-tetrahydrophthalic anhydride (0.53 g) and acetic acid (5 ml) was heated at 100 to 110° C. under reflux for 3 hours. After being allowed to cool, water was added to the mixture, which was then extracted with ethyl acetate. The organic layer was washed with water, neuralized with sodium bicarbonate solution, dried and concentrated to give 2-[3-(2-propynyl)-3H-benzoxazol-2-on-5-yl]-4,5,6,7-tetrahydro-2H-isoindole-1,3-dione (0.30 g). m.p., 285.5° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[NH:12][C:13]([CH:16]=O)=[C:14]([CH3:15])[C:8]=2[C:7]1=[O:18])[CH3:2].[NH:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:35]=[CH:34][CH:33]=[C:32]3[C:28]=2[CH2:29][C:30](=[O:36])[NH:31]3)[CH2:23][CH2:22]1>>[CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[NH:12][C:13]([CH:16]=[C:29]3[C:28]4[C:32](=[CH:33][CH:34]=[CH:35][C:27]=4[CH:24]4[CH2:23][CH2:22][NH:21][CH2:26][CH2:25]4)[NH:31][C:30]3=[O:36])=[C:14]([CH3:15])[C:8]=2[C:7]1=[O:18])[CH3:2]
Reactant: O=C1Cc2c(cccc2C2CCNCC2)N1
Reactant: CCN(CC)CCN1CCc2[nH]c(C=O)c(C)c2C1=O
Product: CCN(CC)CCN1CCc2[nH]c(C=C3C(=O)Nc4cccc(C5CCNCC5)c43)c(C)c2C1=O
Yield: 26 %

Procedure:
The title compound was prepared under the same conditions as described in Example 1 with 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 4-piperidin-4-yl-1,3-dihydro-indol-2-one as starting materials to give 5-(2-diethylamino-ethyl)-3-methyl-2-(2-oxo-4-piperidin-4-yl-1,2-dihydro-indol-3-ylidenemethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (20 mg, 26.0%) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH:7]2[O:12][CH2:11][CH2:10][NH:9][CH2:8]2)[O:4][N:3]=1.Cl[C:14]1[C:15]2[C:22]([C:23]3[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=3)[C:26]#[N:27])=[CH:21][NH:20][C:16]=2[N:17]=[CH:18][N:19]=1>C(O)CCC>[CH3:1][C:2]1[CH:6]=[C:5]([CH:7]2[O:12][CH2:11][CH2:10][N:9]([C:14]3[C:15]4[C:22]([C:23]5[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=5)[C:26]#[N:27])=[CH:21][NH:20][C:16]=4[N:17]=[CH:18][N:19]=3)[CH2:8]2)[O:4][N:3]=1
Reactant: Cc1cc(C2CNCCO2)on1
Reactant: N#Cc1cccc(-c2c[nH]c3ncnc(Cl)c23)c1
Solvent: CCCCO
Product: Cc1cc(C2CN(c3ncnc4[nH]cc(-c5cccc(C#N)c5)c34)CCO2)on1
Temperature: 150 °C

Procedure:
To a solution of 2-(3-methyl-1,2-oxazol-5-yl)morpholine (C38) (20 mg, 0.12 mmol) in n-butanol (7 mL) was added 3-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)benzonitrile (C14) (36.2 mg, 0.142 mol), and the reaction mixture was placed in a sealed tube and heated at 150° C. in a microwave reactor for 2 hours. After removal of solvent, the residue was purified by preparative reversed phase high-performance liquid chromatography (Column: YMC-Actus Triart C18, 5 μm; Mobile phase A: water containing 0.225% formic acid; Mobile phase B: acetonitrile; Gradient: 33% to 53% B) to afford the product as a white solid. Yield: 0.78 mg, 2.0 μmol, 2%. LCMS m/z 387.0[M+H+]. 1H NMR (400 MHz, DMSO-d6), characteristic peaks: δ 12.45 (br s, 1H), 8.45 (s, 1H), 8.00-8.03 (m, 1H), 7.85 (br d, J=8 Hz, 1H), 7.76 (br d, J=8 Hz, 1H), 7.72 (d, J=2.8 Hz, 1H), 7.66 (dd, J=8, 8 Hz, 1H), 6.25 (s, 1H), 4.58-4.63 (m, 1H), 3.71-3.83 (m, 2H), 3.01-3.09 (m, 1H), 2.88-2.97 (m, 1H), 2.20 (s, 3H).
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([NH:16][C:17](=[O:25])OC3C=CC=CC=3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][C:37]=1[O:38][CH3:39])[N:34]=[CH:33][N:32]=[C:31]2[S:40][C:41]1[CH:42]=[C:43]([CH:45]=[CH:46][CH:47]=1)[NH2:44].C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:26][O:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][C:37]=1[O:38][CH3:39])[N:34]=[CH:33][N:32]=[C:31]2[S:40][C:41]1[CH:42]=[C:43]([NH:44][C:17]([NH:16][C:9]2[CH:10]=[C:11]([C:12]([F:13])([F:14])[F:15])[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=2)=[O:25])[CH:45]=[CH:46][CH:47]=1
Reactant: COc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Reactant: O=C(Nc1cc(C(F)(F)F)n(-c2ccccc2)n1)Oc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(F)(F)F)n(-c5ccccc5)n4)c3)c2cc1OC
Yield: 45 %

Procedure:
The title compound was prepared as described in Example 169C, using phenyl 1-phenyl-5-(trifluoromethyl)-1H-pyrazol-3-ylcarbamate described in Example 169B (0.115 g, 0.33 mmol), 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline from Example 115B (0.103 g, 0.33 mmol), and N,N-diisopropylethylamine (0.8 mL) in THF (6 mL), to afford 1-[3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl]-3-[1-phenyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]urea as solid (0.084 g, 45%). 1H NMR (300 MHz, DMSO-d6) δ 9.47 (s, 1H), 9.01 (s, 1H), 8.70 (s, 1H), 7.86 (s, 1H), 7.55 (m, 6H), 7.45 (t, 1H), 7.36 (s, 1H), 7.35 (s, 1H), 7.28 (s, 1H), 7.14 (s, 1H), 4.00 (s, 6H); LC-MS (ESI) m/z 567 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[O:3][C:4]2[C:9]([CH:10]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([Br:24])[CH:15]=3)[C:11]=1[C:12]#[N:13])=[CH:8][CH:7]=[C:6]1[CH:25]=[CH:26][CH:27]=[CH:28][C:5]=21.Cl.[NH2:30][OH:31].C(=O)([O-])[O-].[K+].[K+]>C(O)C.C(OCC)(=O)C>[NH2:1][C:2]1[O:3][C:4]2[C:9]([CH:10]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([Br:24])[CH:15]=3)[C:11]=1[C:12]([NH:30][OH:31])=[NH:13])=[CH:8][CH:7]=[C:6]1[CH:25]=[CH:26][CH:27]=[CH:28][C:5]=21
Reactant: COc1cc(C2C(C#N)=C(N)Oc3c2ccc2ccccc32)cc(Br)c1OC
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1cc(C2C(C(=N)NO)=C(N)Oc3c2ccc2ccccc32)cc(Br)c1OC
Reaction time: 48 h

Procedure:
2-Amino-4-(3-bromo-4,5-dimethoxy-phenyl)-4H-benzo[h]chromene-3-carbonitrile (1) (4.38 g, 10 mmol), hydroxylamine hydrochloride (2.80 g, 40 mmol) and potassium carbonate (2.80 g, 1 mmol) were suspended in 80 ml ethanol at room temperature then stirred under LC-MS control 48 h. The reaction was clean with a minor side product (<3%). The reaction mixture was diluted with ethyl acetate to about 150 ml and stirred for 2 h at room temperature. Thus resulting insoluble salt was separated by filtration, washed well with ethyl acetate and the combined organic solution was evaporated to dryness at 40° C. under vacuum and the residue was dried under high vacuum to get solids (4.70 g, 10 mmol, 100% theoretical yield) of the title compound.
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[N:15]=[CH:16][N:17]([C:19]3[N:24]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=4)[CH:22]=[C:21]([CH3:33])[N:20]=3)[CH:18]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:32][C:27]1[CH:26]=[C:25]([C:23]2[CH:22]=[C:21]([CH3:33])[N:20]=[C:19]([N:17]3[CH:18]=[C:14]([C:11]4[S:10][C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:13][CH:12]=4)[N:15]=[CH:16]3)[N:24]=2)[CH:30]=[CH:29][C:28]=1[Cl:31]
Reactant: Cc1cc(-c2ccc(Cl)c(Cl)c2)nc(-n2cnc(-c3ccc(S(=O)(=O)NC(C)(C)C)s3)c2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2ccc(Cl)c(Cl)c2)nc(-n2cnc(-c3ccc(S(N)(=O)=O)s3)c2)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 76.5 %

Procedure:
To a cooled and stirred solution of 5-{1-[4-(3,4-dichloro-phenyl)-6-methyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-thiophene-2-sulfonic acid tert-butyl amide (0.41 g) in dichloromethane (5 mL) was added TFA (5 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (10 mL) was added. The mixture was stirred at room temperature for 30 min, the precipitate was collected by filtration and washed with water. The crude product was further purified by crystallization (MeOH/diethyl ether) to yield the title compound as a light brown solid (0.28 g, 79%). MS (ISP) 466.1 [(M+H)+]; mp 253.5° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][C:28]([O:30]CC4C=CC=CC=4)=[O:29])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].CO.[OH-].[Na+]>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][C:28]([OH:30])=[O:29])=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CC(=O)OCc4ccccc4)cc3)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CC(=O)O)cc3)cc2)CC1
Reaction time: 1.5 h

Procedure:
1-[4′-(4-Benzyloxycarbonylmethyl-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester (0.171 g, 0.35 mmol) was stirred in THF (3 mL) and MeOH (3 mL) and 1 N aqueous NaOH (1 mL) was added. After 1.5 hours the reaction was submitted to standard aqueous workup to afford the title compound.