Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[S:3][C:2]=1[SH:10].[F:11][C:12]([F:18])=[C:13]([F:17])[CH2:14][CH2:15]Br.C(=O)([O-])[O-].[K+].[K+].O>C(N(CC)C=O)C>[F:17][C:13](=[C:12]([F:18])[F:11])[CH2:14][CH2:15][S:10][C:2]1[S:3][C:4]2[C:9]([N:1]=1)=[CH:8][CH:7]=[CH:6][N:5]=2
Reactant: FC(F)=C(F)CCBr
Reactant: Sc1nc2cccnc2s1
Agent: CCN(C=O)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: FC(F)=C(F)CCSc1nc2cccnc2s1
Temperature: 60 °C
Reaction time: 24 h
Yield: 87.4 %

Procedure:
A solution of thiazolo[5,4-b]pyridine-2-thiol (6.2 g) in N,N-diethyl formamide under nitrogen was treated with 1,1,2-trifluoro-4-bromobutene (8.3 g) and potassium carbonate (1.5 g), stirred at 60° C. for 24 hours, cooled, and poured into water. The resultant aqueous mixture was extracted with diethyl ether. The organic extract was dried over anhydrous sodium sulfate and concentrated in vacuo to obtain a residue. Column chromatography of the residue using silica gel and a 9:1 hexanes/ethyl acetate solution gave the title product as a colorless oil (8.9 g).
Reaction SMILES: C(O[CH:5]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:12][C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)(=O)C.[CH2:19]([N:21]1[CH2:26][CH2:25][CH2:24][CH:23]([NH:27][CH3:28])[CH2:22]1)[CH3:20]>C1C=CC=CC=1>[CH3:28][N:27]([CH:5]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=2[O:12][C:13]2[C:18]1=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:23]1[CH2:24][CH2:25][CH2:26][N:21]([CH2:19][CH3:20])[CH2:22]1
Reactant: CC(=O)OC1c2ccccc2Oc2ccccc21
Reactant: CCN1CCCC(NC)C1
Solvent: c1ccccc1
Product: CCN1CCCC(N(C)C2c3ccccc3Oc3ccccc32)C1
Temperature: 25 °C

Procedure:
A solution of 3.7 g. (15.4 mmoles) of 9-acetoxyxanthene and 2.2 g. (15.5 mmoles) of 1-ethyl-3-methylaminopiperidine in 80 ml. of benzene was refluxed under nitrogen for 22.5 hours. It was then cooled to room temperature, washed with aqueous sodium bicarbonate solution, and dried over potassium carbonate. After removal of solvent in vacuo, the residue was dissolved in 25 ml. of petroleum ether and filtered from a small amount of crystals. The filtrate was then concentrated in vacuo and chromatographed on silica gel (ether solvent) to give N-methyl-N-(N-ethyl-3-piperidinyl)-9-xanthenylamine.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[F:7][CH2:8][CH2:9][O:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[C:13]#[N:14]>>[F:7][CH2:8][CH2:9][O:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13][NH2:14]
Reactant: N#Cc1ccccc1OCCF
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: NCc1ccccc1OCCF
Temperature: 0 °C
Reaction time: 4.5 h

Procedure:
LiAlH4 (3.4 mL, 2M solution in THF) was added to a solution of compound 135 (114 mg, 0.69 mmol) at 0° C. and then the mixture was brought to room temperature and stirred for 4.5 h. After completion of reaction, the reaction mixture was cooled to 0° C. and carefully quenched the reaction with a saturated solution of potassium-sodium tartarate tetrahydrate by dropwise addition. The reaction mixture was filtered on a Celite bed and the filtrate was dried (Na2SO4) filtered and evaporated. The residue was purified on flash silica gel column chromatography (CH2Cl2:MeOH:NH4OH=25:1:0.1) to yield the compound 136a (which was contaminated minor amount of fluorine reduced product), yield 86 mg (74%) as a colorless syrup. 1H NMR (CD3OD, 300 MHz) δ 7.19-7.25 (m, 2H), 6.87-6.97 (m, 2H), 4.66-4.69 (m, 1H), 4.29-4.32 (m, 1H), 4.20-4.22 (m, 1H), 4.02-4.11 (m, 1H), 3.75-3.79 (m, 2H). HRMS calculated for C9H13NOF (M+H)+: 170.0981. found 170.0982. Compound 136b was prepared in a similar manner.
Reaction SMILES: C(OP([C:9]([O:25][CH3:26])([O:23][CH3:24])[CH2:10][CH2:11][C:12]1[CH:22]=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=1)(OCC)=O)C.[Li]CCCC.[CH3:32][C:33]1[S:37][C:36]([C:38]2[C:47]3[C:42](=[CH:43][CH:44]=[C:45]([CH:48]=O)[CH:46]=3)[C:41]([CH3:51])([CH3:50])[CH2:40][CH:39]=2)=[CH:35][CH:34]=1>C1COCC1.CCOCC>[CH3:26][O:25][CH:9]([O:23][CH3:24])[CH2:10]/[C:11](/[C:12]1[CH:13]=[CH:14][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:21][CH:22]=1)=[CH:48]\[C:45]1[CH:46]=[C:47]2[C:42]([C:41]([CH3:51])([CH3:50])[CH2:40][CH:39]=[C:38]2[C:36]2[S:37][C:33]([CH3:32])=[CH:34][CH:35]=2)=[CH:43][CH:44]=1
Reactant: Cc1ccc(C2=CCC(C)(C)c3ccc(C=O)cc32)s1
Reactant: CCOC(=O)c1ccc(CCC(OC)(OC)P(=O)(OCC)OCC)cc1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(/C(=C/c2ccc3c(c2)C(c2ccc(C)s2)=CCC3(C)C)CC(OC)OC)cc1
Temperature: -10 °C
Reaction time: 0.17 h

Procedure:
To a cold (-78° C.) solution of ethyl 4-(diethoxyphosphoryl-3,3-dimethoxypropyl)benzoate (Compound D, 1.4 g, 3.6 mmol), in THF (20 mL) was added n-BuLi (1.6M solution in hexane, 2.5 mL, 4 mmol). The mixture was stirred for 20 minutes at -78° C. and 10 min. at -10° C. The reaction mixture was recooled to -78° C. and 1(5-methyl-thien-2-yl)3,4-dihydro-4,4-dimethyl-7-naphthaldehyde (Compound G, 650 mg, 2.3 mmol) in THF (4 mL) was added to it. The mixture was stirred for 2 hours at -10° C. and diluted with ether (100 mL), washed with brine (10 mL) dried with MgSO4 and the solvent was removed by distillation to to afford a cis and trans (E and Z) isomeric mixture. Purification by chromatography on silica gel of the crude material afforded the title compound as an off (~ 90% purity).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([O:10]C)[CH:7]=[CH:6][C:4]=1[NH2:5].C[O:13][C:14]1[CH:22]=[CH:21][C:17](C(Cl)=O)=[CH:16][CH:15]=1>>[OH:13][C:14]1[CH:22]=[CH:21][C:17]([C:1]2[O:2][C:3]3[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:4]=3[N:5]=2)=[CH:16][CH:15]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: COc1ccc(N)c(OC)c1
Product: Oc1ccc(-c2nc3ccc(O)cc3o2)cc1

Procedure:
The title compound was prepared in substantially the same manner as described in Example 1, from 2,4-dimethoxyaniline, and 4-methoxybenzoyl chloride and was obtained as a white solid, m.p. greater than 300° C.; MS m/e 226 (M−H)+.
Reaction SMILES: C[O:2][C:3](=[O:39])[C@@H:4]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]4[S:27][CH:28]=[CH:29][N:30]=4)=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)=[CH:8][CH:7]=1.[OH-].[Na+]>C1COCC1.O>[C:35]([O:34][C:32]([NH:31][C@@H:4]([CH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:21]=[CH:22][C:23]([C:26]4[S:27][CH:28]=[CH:29][N:30]=4)=[CH:24][CH:25]=3)=[CH:15][CH:14]=2)=[CH:10][CH:11]=1)[C:3]([OH:39])=[O:2])=[O:33])([CH3:38])([CH3:36])[CH3:37]
Reactant: COC(=O)[C@H](Cc1ccc(Oc2ccc(Oc3ccc(-c4nccs4)cc3)cc2)cc1)NC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(Oc2ccc(Oc3ccc(-c4nccs4)cc3)cc2)cc1)C(=O)O
Yield: 88.7 %

Procedure:
A solution of the product from step 6 (0.4 g, 0.72 mmol) and NaOH (62 mg, 1.54 mmol) in THF/water (1:1, 10 mL) was stirred at room temperature for 16 h. After the THF was removed, the aqueous solution was acidified with 10% HCl to pH=2, the solid was collected on a filter to yield the title compound (340 mg, 82%). 1HNMR (CDCl3) δ 1.42 (s, 9H), 3.15 (m, 2H), 4.57 (m, 1H), 5.00 (m, 1H), 6.95 (d, J=8.8 Hz, 2H), 7.02-7.15 (m, 6H), 7.17 (d, J=8.8 Hz, 2H), 7.30 (d, J=3.2 Hz, 1H), 7.85 (d, J=3.2 Hz, 1H), 7.91 (d, J=8.8 Hz, 2H).
Reaction SMILES: [C:1]([O:9]CC)(=[O:8])[CH2:2][C:3](OCC)=O.[H-].[Na+].ClC[C:16]1[CH:17]=[N:18][O:19][C:20]=1[C:21]1[S:22][C:23]([Cl:27])=[C:24]([Cl:26])[CH:25]=1.Cl>O1CCCC1.O>[Cl:26][C:24]1[CH:25]=[C:21]([C:20]2[O:19][N:18]=[CH:17][C:16]=2[CH2:3][CH2:2][C:1]([OH:9])=[O:8])[S:22][C:23]=1[Cl:27]
Reactant: ClCc1cnoc1-c1cc(Cl)c(Cl)s1
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCc1cnoc1-c1cc(Cl)c(Cl)s1
Reaction time: 0.17 h
Yield: 78.8 %

Procedure:
To a solution of diethyl malonate (3.55 g) in tetrahydrofuran (50 ml) was gradually added sodium hydride (60%, oil, 710 mg) at 0° C. The mixture was stirred for 10 min and a solution of 4-chloromethyl-5-(4,5-dichloro-2-thienyl)isoxazole (2.38 g) in tetrahydrofuran (50 ml) was added dropwise at 0° C. The mixture was stirred at room temperature for 15 hr. The reaction mixture was poured into water, acidified with 2N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was dissolved in a mixture of 6N hydrochloric acid (60 ml) and acetic acid (90 ml), and the solution was heated under reflux for 8 hr. The reaction mixture was concentrated, and water was added to the residue to give colorless crystals (2.04 g, yield 79%) of 3-[5-(4,5-dichloro-2-thienyl)-4-isoxazolyl]propionic acid. The crystals were recrystallized from ethyl acetate-hexane to give a colorless prism. melting point: 142–143° C.
Reaction SMILES: N(OCCC(C)C)=O.N[C:10]1[C:11]([Cl:26])=[CH:12][C:13]([F:25])=[C:14]([C:16]2[C:20]([CH3:21])=[C:19]([C:22]#[N:23])[N:18]([CH3:24])[N:17]=2)[CH:15]=1.[I:27]CI>>[Cl:26][C:11]1[C:10]([I:27])=[CH:15][C:14]([C:16]2[C:20]([CH3:21])=[C:19]([C:22]#[N:23])[N:18]([CH3:24])[N:17]=2)=[C:13]([F:25])[CH:12]=1
Reactant: Cc1c(-c2cc(N)c(Cl)cc2F)nn(C)c1C#N
Reactant: ICI
Agent: CC(C)CCON=O
Product: Cc1c(-c2cc(I)c(Cl)cc2F)nn(C)c1C#N
Temperature: 22 °C
Reaction time: 14 h

Procedure:
5.86 g of isoamyl nitrite are added dropwise at a temperature of below 15° C. to a solution of 2.64 g of 3-(5-amino-4-chloro-2-fluoro-phenyl)-4-methyl-5-cyano-1-methyl-[1H]-pyrazole in 54 g (16 ml) of diiodomethane. The reaction mixture is stirred for 14 hours at 22° C., and excess diiodomethane is evaporated in vacuo. All the diiodomethane is subsequently distilled off at 70-75° C./14 torr, and the crude product is purified over a silica gel column (eluent: ethyl acetate/hexane 1/5). The desired product is obtained in a yield of 1.88 g (50.2% of theory).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([NH:18][C:19](=[O:33])[C:20]([C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=2)=[CH:21][O:22][CH:23]([F:25])[F:24])[CH3:17])=[CH:11][C:10]=1[O:34][CH3:35])C1C=CC=CC=1.Br>C(O)(=O)C>[F:24][CH:23]([F:25])[O:22][CH:21]=[C:20]([C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1)[C:19]([NH:18][CH:16]([CH3:17])[CH2:15][C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([O:34][CH3:35])[CH:11]=1)=[O:33]
Reactant: COc1cc(CC(C)NC(=O)C(=COC(F)F)c2ccc(C)cc2)ccc1OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Product: COc1cc(CC(C)NC(=O)C(=COC(F)F)c2ccc(C)cc2)ccc1O
Temperature: 80 °C
Reaction time: 2 h
Yield: 75.1 %

Procedure:
1.80 g (3.74 mmol) of N-[2-(4-benzyloxy-3-methoxyphenyl)-1-methylethyl]-3-difluoromethoxy-2-(4-methylphenyl)acrylamide, 693 mg (4.11 mmol) of 48% hydrobromic acid and 20 ml of acetic acid were mixed and stirred at 80° C. for 2 hours. The solvent was distilled off from the reaction mixture under reduced pressure and the residue was subjected to silica gel column chromatography (eluent, hexane:ethyl acetate=2:1) to give 1.10 g of 3-difluoromethoxy-N-[2-(4-hydroxy-3-methoxyphenyl)-1-methylethyl]-2-(4-methylphenyl)acrylamide.
Reaction SMILES: C(O[CH:4](OCC)[N:5]1[CH2:9][CH2:8][NH:7][C:6]1=[N:10][N+:11]([O-:13])=[O:12])C.[NH2:17][C:18]1[C:19]([CH3:24])=[CH:20][CH:21]=[CH:22][CH:23]=1.C1COCC1.O>CCOCC>[CH3:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[N:17]=[CH:4][N:5]1[CH2:9][CH2:8][NH:7][C:6]1=[N:10][N+:11]([O-:13])=[O:12]
Reactant: CCOC(OCC)N1CCNC1=N[N+](=O)[O-]
Reactant: Cc1ccccc1N
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1ccccc1N=CN1CCNC1=N[N+](=O)[O-]

Procedure:
A mixture of 2.0 g of of 1-diethoxymethyl-2-nitroiminoimidazolidine, 0.92 g of o-toluidine, 5 ml of THF and 0.12 g of a boron trifluoride ether complex was heated under reflux for 1 hour. The reaction mixture was poured into water, extracted with ethyl acetate, washed with water, dried and condensed. Ether was added to the resultant oily residue and the resultant crystals were separated by filtration and dried to give 1.2 g of 1-(2-methylphenyliminomethyl)-2-nitroiminoimidazolidine.
Reaction SMILES: Cl[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[NH2:18][C:19]1[C:32]2[C:31](=[O:33])[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24](=[O:34])[C:23]=2[C:22](N)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>[N+](C1C=CC=CC=1)([O-])=O.Cl[Cu]>[CH:10]1[CH:9]=[C:8]2[C:7]([C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([NH:18][C:19]4[C:32]5[C:31]([C:30]6[C:25]([C:24](=[O:34])[C:23]=5[CH:22]=[CH:21][CH:20]=4)=[CH:26][CH:27]=[CH:28][CH:29]=6)=[O:33])[C:15]=3[C:14](=[O:16])[C:13]2=[CH:12][CH:11]=1)=[O:17]
Reactant: Nc1ccc(N)c2c1C(=O)c1ccccc1C2=O
Reactant: O=C1c2ccccc2C(=O)c2c(Cl)cccc21
Agent: Cl[Cu]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C1c2ccccc2C(=O)c2c(Nc3cccc4c3C(=O)c3ccccc3C4=O)cccc21

Procedure:
Following the procedure as descrilbed in Example 1, but suspending the 1-chloroanthraquinone, 1,4-diaminoanthraquinone, sodium carbonate and CuCl in 300 ml of nitrobenzene, the anthrimide is obtained in a yield corresponding to that of Example 1. When following a conventional procedure, i.e. mixing the components and heating them slowly, if such a concentrated reaction mixture is employed, the reaction can no longer be carried out in an agitator vessel.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([F:14])[C:12]=1[CH3:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH2:15]([N:17](C(C)C)C(C)C)[CH3:16].BrCC#N>C1COCC1>[C:15]([CH2:16][NH:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([F:14])[C:12]=1[CH3:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6])#[N:17]
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOC(=O)c1cc(N)c(C)c(F)c1
Agent: N#CCBr
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(F)c(C)c(NCC#N)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirred solution of 3-amino-5-fluoro-4-methyl-benzoic acid, ethyl ester (Example 169b, 1.2 g) in THF (10 mL) at room temperature was added N-ethyldiisopropylamine (1.28 mL) followed by bromoacetonitrile (0.51 mL) and the reaction was heated at reflux for 14 h. Additional bromoacetonitrile (0.21 mL) was added and the mixture was heated at reflux for 6 h. Further bromoacetonitrile (0.21 mL) was added and heating was continued for a further 12 h. After cooling to room temperature the reaction was concentrated. Aqueous HCl (30 mL, 1N) and ethyl acetate (30 mL) were added. The layers were separated and the organic fraction was dried (Na2SO4), filtered and concentrated to give the subtitle product (1.43 g) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=[C:10]([N:18]3[CH:22]=[C:21](I)[N:20]=[CH:19]3)[N:9]=2)=[CH:4][CH:3]=1.[C:24]([NH:28][S:29]([C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1)(=[O:31])=[O:30])([CH3:27])([CH3:26])[CH3:25]>>[C:24]([NH:28][S:29]([C:32]1[CH:33]=[CH:34][CH:35]=[C:36]([C:21]2[N:20]=[CH:19][N:18]([C:10]3[N:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:9]=3)[CH:22]=2)[CH:37]=1)(=[O:31])=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)cc2)nc(-n2cnc(I)c2)n1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2cn(-c3nc(-c4ccc(Cl)cc4)cc(C(F)(F)F)n3)cn2)c1

Procedure:
N-tert-Butyl-3-{1-[6-(4-chloro-phenyl)-4-trifluoromethyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-benzenesulfonamide was prepared from 4-(4-chloro-phenyl)-2-(4-iodo-imidazol-1-yl)-6-trifluoromethyl-pyrimidine (example E.70) (0.68 g, 1.5 mmol) and commercially available 3-(tert.-butylsulfamoyl)-phenylboronic acid (0.46 g, 1.8 mmol) according to the general procedure VI. Obtained as a light yellow solid (0.34 g) which was subsequently deprotected.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[F:25][C:26]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:27]=1[CH2:28]Br.C(OC(N1CCC2C(=C(C3C=CC(Cl)=CC=3)N(CC3C=CC(F)=CC=3F)N=2)CC1)=O)(C)(C)C>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH2:28][C:27]3[CH:30]=[CH:31][C:32]([F:34])=[CH:33][C:26]=3[F:25])[N:13]=2)=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Reactant: Fc1ccc(CBr)c(F)c1
Agent: CC(C)(C)OC(=O)N1CCc2nn(Cc3ccc(F)cc3F)c(-c3ccc(Cl)cc3)c2CC1
Product: Fc1ccc(Cn2nc(-c3ccc(Cl)cc3)c3c2CCNCC3)c(F)c1
Yield: 40.1 %

Procedure:
The title compound (0.030 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B; 0.2 mmol) using 2,4-difluorobenzyl bromide (0.3 mmol) in place of 2-chloromethyl-thiophene. The reaction sequence also yielded 3-(4-chloro-phenyl)-2-(2,4-difluoro-benzyl)-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester in the alkylation step. MS (ESI): exact mass calculated for C20H18ClF2N3, 373.12. found, m/z 374.1 [M+H]+. 1H NMR (400 MHz, CD3OD): 7.52-7.49 (br m, 4H), 7.27-7.24 (br m, 1H), 7.01-6.99 (br m, 2H), 5.52 (s, 2H), 3.51-3.49 (br m, 2H), 3.43-3.40 (br m, 2H), 3.34-3.31 (br m, 2H), 3.11-3.09 (br m, 2H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH:6]=O)=[CH:2]1.[CH3:8][C:9]1([CH3:16])[C:13](=[O:14])[CH:12]=[C:11]([CH3:15])[O:10]1.[OH-].[Cl-].[Na+]>C(O)C>[O:1]1[CH:5]=[CH:4][C:3]([CH:6]=[CH:15][C:11]2[O:10][C:9]([CH3:16])([CH3:8])[C:13](=[O:14])[CH:12]=2)=[CH:2]1
Reactant: CC1=CC(=O)C(C)(C)O1
Reactant: O=Cc1ccoc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)OC(C=Cc2ccoc2)=CC1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 74.1 %

Procedure:
To a solution of 3-furaldehyde (1.26 g, 13.2 mM) and 2,2,5-trimethyl-3(2H)-furanone (1.5 g, 11.9 mM) in ethanol (50 mL), was added 1N aqueous hydroxide (1.2 mL, 1.2 mM). After the reaction solution was stirred for one day at room temperature, saturated aqueous sodium chloride (400 mL) was added. The aqueous layer was extracted with diethyl ether (3×100 mL). The combined ethereal extracts were washed with saturated aqueous sodium chloride (50 mL), dried over MgSO4, filtered and concentrated to give a yellow solid. The crude product was purified by chromatography (silica gel, hexane-ethyl acetate) to yield yellow crystals (1.8 g, 74% yield), m.p. 79°-80° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH:5]=[CH:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[O:14][CH3:15])[CH3:2]>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][CH2:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[O:14][CH3:15])[CH3:2]
Reactant: CCOC(=O)C=Cc1cc(F)ccc1OC
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1cc(F)ccc1OC
Reaction time: 20 h
Yield: 94.9 %

Procedure:
To a solution of ethyl-3-(5′-fluoro-2′-methoxyphenyl)acrylate (6.0 g, 27 mmol) in ethanol (100%, 80 mL) under Ar was added Pd/C (10%, 250 mg) very carefully and the flask containing the mixture was evacuated and purged with H2 three time each. Then a H2 balloon was attached to the flask and charged with H2 and the reaction was allowed to go for 20 h at room temperature. Then the reaction mixture was filtered through a pad of silica eluted with mixed solvent of EtOAc and Hexane (1:1). The crude product that obtained by removal of the solvent in vacuo was purified by flash column chromatography (10% EtOAc in hexane, Rf=0.20) to give the product (5.8 g, 95%).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.Cl.[CH3:18][N:19]([CH3:24])[CH2:20][CH2:21][CH2:22]Cl.[C:25]([OH:32])(=[O:31])/[CH:26]=[CH:27]/[C:28]([OH:30])=[O:29]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(#N)C.O.C(O)C>[C:25]([OH:32])(=[O:31])/[CH:26]=[CH:27]/[C:28]([OH:30])=[O:29].[C:25]([OH:32])(=[O:31])/[CH:26]=[CH:27]/[C:28]([OH:30])=[O:29].[CH3:18][N:19]([CH3:24])[CH2:20][CH2:21][CH2:22][N:12]1[CH2:11][CH2:10][CH:9]([C:6]2[C:5]3[CH:15]=[CH:16][C:2]([F:1])=[CH:3][C:4]=3[O:8][N:7]=2)[CH2:14][CH2:13]1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: CN(C)CCCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C(O)/C=C/C(=O)O
Solvent: CC#N
Solvent: O
Solvent: CCO
Product: CN(C)CCCN1CCC(c2noc3cc(F)ccc23)CC1
Temperature: 60 °C
Yield: 56.9 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (3.05 g, 13.8 mmol), 3-dimethylaminopropyl chloride hydrochloride (3.4 g, 21 mmol), K2O3 (6.2 g, 45 mmol), tetrabutylammonium hydrogen sulfate (phase transfer catalyst, 1.5 g) in acetonitrile (100 ml) and water (50 ml) was heated at 60° C. overnight. The aqueous phase was separated, and acetonitrile was removed at reduced pressure. The residue was extracted into DCM. The organic solution was washed with H2O and brine, then dried with MgSO4. The solvent was removed and the crude product (4.3 g) was treated with fumaric acid (1.58 g, 1.0 eq) in dilute ethanol. The crystals were collected (2.53 g), m.p.=192°-194° C. Recrystallization from ethanol yielded 2.08 g of white crystals, mp=194°-195° C.
Reaction SMILES: [CH3:1][CH:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([NH2:11])[C:5]=2[CH2:4][C:3]21[CH2:15][CH2:14][CH2:13][CH2:12]2.C(N(CC)CC)C.[Cl:23][C:24]1[N:28]([CH3:29])[N:27]=[C:26]([CH:30]([F:32])[F:31])[C:25]=1[C:33](Cl)=[O:34]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:23][C:24]1[N:28]([CH3:29])[N:27]=[C:26]([CH:30]([F:31])[F:32])[C:25]=1[C:33]([NH:11][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[CH2:4][C:3]1([CH2:12][CH2:13][CH2:14][CH2:15]1)[CH:2]2[CH3:1])=[O:34]
Reactant: Cn1nc(C(F)F)c(C(=O)Cl)c1Cl
Reactant: CC1c2cccc(N)c2CC12CCCC2
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1c2cccc(NC(=O)c3c(C(F)F)nn(C)c3Cl)c2CC12CCCC2
Reaction time: 4 h
Yield: 64 %

Procedure:
In a 25 ml round bottom flask, a solution of 1′-methyl-1′,3′-dihydrospiro[cyclopentane-1,2′-inden]-4′-amine in 5 ml of DCM is cooled to 0° C. and triethylamine (0.104 ml, 0.745 mmol, 1.5 eq) is added followed by DMAP (6 mg, 0.05 mmol, 0.1 eq). A solution of 5-chloro-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbonyl chloride (125 mg, 0.546 mmol, 1.1 eq) in 1 ml of DCM is added dropwise. Stirring is allowed for 4 h at r.t. The reaction is quenched with 1N aq. HCl, and diluted with EtOAc. The aqueous layer was separated and extracted with EtOAc. The organics were combined, washed with NaOH 1N, dried over MgSO4 and concentrated. The crude material was purified by chromatography on silica gel to give pure material (64%)
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[NH:6][N:7]=[C:8]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:11](=[O:18])[C:10]=1[C:9]=23.[CH3:19][NH:20][CH3:21]>N1C=CC=CC=1>[CH3:19][N:20]([CH3:21])[C:2]1[CH:3]=[CH:4][C:5]2[NH:6][N:7]=[C:8]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:11](=[O:18])[C:10]=1[C:9]=23
Reactant: O=C1c2ccccc2-c2n[nH]c3ccc(Cl)c1c23
Reactant: CNC
Solvent: c1ccncc1
Product: CN(C)c1ccc2[nH]nc3c2c1C(=O)c1ccccc1-3
Temperature: 100 °C

Procedure:
A mixture of 5-chloroanthra[1,9cd]pyrazol-6(2H)-one (Example 1-B) and dimethylamine in pyridine is heated at 100° C. for 16 hours. The mixture is cooled and evaporated. The residue is chromatographed on silica gel to give the desired compound as yellow solids.
Reaction SMILES: [C:1]([C:5]1[CH:31]=[CH:30][C:8]([C:9]([NH:11][C:12]2[CH:28]=[C:27]([NH2:29])[CH:26]=[CH:25][C:13]=2[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[O:15])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:32][O:33][CH2:34][C:35](Cl)=[O:36]>>[C:1]([C:5]1[CH:31]=[CH:30][C:8]([C:9]([NH:11][C:12]2[CH:28]=[C:27]([NH:29][C:35](=[O:36])[CH2:34][O:33][CH3:32])[CH:26]=[CH:25][C:13]=2[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[O:15])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(NC(=O)c2ccc(N)cc2NC(=O)c2ccc(C(C)(C)C)cc2)cc1
Reactant: COCC(=O)Cl
Product: COCC(=O)Nc1ccc(C(=O)Nc2ccc(OC)cc2)c(NC(=O)c2ccc(C(C)(C)C)cc2)c1
Yield: 74 %

Procedure:
Using the procedure described in Example 59, Part E, 2-(4-tert-butylbenzoylamino)-4-amino-N-(4-methoxyphenyl)benzamide was reacted with methoxyacetyl chloride (0.55 mmol) to yield 175 mg (74%) of the title compound as a solid.