Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li]CCCC.[C:6](Br)([CH3:8])=[CH2:7].CON(C)[C:13](=[O:30])[C@@H:14]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:15][CH:16]1[CH2:20][CH2:19][NH:18][C:17]1=[O:21].[NH4+].[Cl-]>C1COCC1>[CH3:8][C:6](=[CH2:7])[C:13](=[O:30])[C@@H:14]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:27])[CH3:28])[CH2:15][CH:16]1[CH2:20][CH2:19][NH:18][C:17]1=[O:21]
Reactant: CON(C)C(=O)[C@H](CC1CCNC1=O)NC(=O)OC(C)(C)C
Reactant: C=C(C)Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=C(C)C(=O)[C@H](CC1CCNC1=O)NC(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 42.7 %

Procedure:
n-BuLi (2.5 M, 3.17 mL, 7.9 mmol) was added dropwise to a solution of isopropenyl bromide (0.9 g, 8.3 mmol) in THF (15.0 mL) at −78° C. and the mixture was stirred at −78° C. for 30 min. A solution of tert-butyl ((2S)-1-(methoxy(methyl)amino)-1-oxo-3-(2-oxopyrrolidin-3-yl) propan-2-yl)carbamate (500 mg, 1.58 mmol) in THF (5.0 mL) was added dropwise. The reaction mixture was stirred at −78° C. for 3 h and then allowed to warm to ambient temperature and stirred for 12 h. Saturated aqueous NH4Cl (50 mL) was added and the resulting mixture was extracted with EtOAc (50 mL×2). The combined extracts were washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc=20:1) to afford tert-butyl ((2S)-4-methyl-3-oxo-1-(2-oxopyrrolidin-3-yl)pent-4-en-2-yl)carbamate (200 mg, 42% yield) as a yellow oil.
Reaction SMILES: [CH3:1][CH:2]([CH3:14])[CH2:3][C:4]1[S:5][C:6]([C:9](OCC)=[O:10])=[CH:7][N:8]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C1COCC1>[OH:10][CH2:9][C:6]1[S:5][C:4]([CH2:3][CH:2]([CH3:14])[CH3:1])=[N:8][CH:7]=1
Reactant: CCOC(=O)c1cnc(CC(C)C)s1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)Cc1ncc(CO)s1
Temperature: 22.5 °C
Reaction time: 1 h

Procedure:
A solution of ethyl 2-(2-methylpropyl)thiazole-5-carboxylate (2.05 g, 9.6 mmol) in THF (10 mL) is added dropwise with stirring to a suspension of lithium aluminum hydride (730 mg, 19 mmol) in dry THF (50 mL) at 0 degrees C. Upon complete addition, the reaction mixture is allowed to stir at 20-25 degrees C. The reaction mixture is cooled to 0 degrees C., and water (0.75 mL), aqueous sodium hydroxide (15%, 0.75 mL), and water (2.25 mL) is added in succession. This mixture is stirred at 0 degrees C. for 1 hour, then filtered through diatomaceous earth, (THF and chloroform). The filtrate is concentrated to give 5-hydroxymethyl-2-(2-methylpropyl)thiazole, MS(ESI): MH+: 172.1.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[C:5]([Cl:21])=[CH:4][N:3]=1.[CH2:22]([N:29]1[CH2:34][CH2:33][P:32]([C:36]2[CH:42]=[CH:41][C:39]([NH2:40])=[C:38]([O:43][CH3:44])[CH:37]=2)(=[O:35])[CH2:31][CH2:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.Cl.[OH-].[Na+]>COCCO>[CH2:22]([N:29]1[CH2:30][CH2:31][P:32]([C:36]2[CH:42]=[CH:41][C:39]([NH:40][C:2]3[N:7]=[C:6]([NH:8][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[C:5]([Cl:21])=[CH:4][N:3]=3)=[C:38]([O:43][CH3:44])[CH:37]=2)(=[O:35])[CH2:33][CH2:34]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COc1cc(P2(=O)CCN(Cc3ccccc3)CC2)ccc1N
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: COCCO
Product: COc1cc(P2(=O)CCN(Cc3ccccc3)CC2)ccc1Nc1ncc(Cl)c(Nc2ccccc2S(=O)(=O)C(C)C)n1
Temperature: 90 °C
Yield: 51.7 %

Procedure:
To a solution of 2,5-dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]pyrimidin-4-amine (47.3 mg, 0.137 mmol) in 1.5 mL of 2-methoxyethanol was added 4-(1-benzyl-4-oxido-1,4-azaphosphinan-4-yl)-2-methoxyaniline (43.0 mg, 0.13 mmol) and ethanolic HCl (0.10 mL, 2.5 M). The mixture was heated in a sealed vial at 90° C. for 16 h. The reaction was then heated at 100° C. for an additional 2 h. The mixture was basified with 1N NaOH solution, and extracted with ethyl acetate. The organic layers were combined, washed with saturated sodium chloride solution, dried with sodium sulfate, filtered and concentrated. The crude residue was purified by silica gel chromatography (0-12% 7N ammonia in methanol:dichloromethane) to afford the desired product (43.0 mg, 52% yield).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:22]=[C:9]2[C:10](=[O:21])[N:11]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[CH2:12][CH2:13][N:8]2[N:7]=1)=O)C.C1(CN2CCN3N=C(CO)C=C3C2=O)CC1>>[F:20][C:17]1[CH:18]=[CH:19][C:14]([N:11]2[CH2:12][CH2:13][N:8]3[N:7]=[C:6]([CH2:4][OH:3])[CH:22]=[C:9]3[C:10]2=[O:21])=[CH:15][CH:16]=1
Reactant: CCOC(=O)c1cc2n(n1)CCN(c1ccc(F)cc1)C2=O
Agent: O=C1c2cc(CO)nn2CCN1CC1CC1
Product: O=C1c2cc(CO)nn2CCN1c1ccc(F)cc1

Procedure:
The compound was prepared from 5-(4-fluorophenyl)-4-oxo-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazine-2-carboxylic acid ethyl ester using the method described in the preceding example 50 (5-cyclopropylmethyl-2-hydroxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[CH:24]=[N:25][N:26]([CH3:29])[C:27]=4[CH3:28])=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:30].[CH3:31][N:32]1[CH2:37][CH2:36][N:35]([C:38]2[CH:43]=[CH:42][C:41]([NH2:44])=[CH:40][CH:39]=2)[CH2:34][CH2:33]1>C1COCC1>[CH3:31][N:32]1[CH2:33][CH2:34][N:35]([C:38]2[CH:43]=[CH:42][C:41]([NH:44][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][C:8]([C:12]([C:14]5[CH:15]=[C:16]([NH:20][C:21]([C:23]6[CH:24]=[N:25][N:26]([CH3:29])[C:27]=6[CH3:28])=[O:22])[CH:17]=[CH:18][CH:19]=5)=[O:13])=[CH:9][CH:10]=4)[NH:5][C:4]3=[O:30])=[CH:40][CH:39]=2)[CH2:36][CH2:37]1
Reactant: Cc1c(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)cnn1C
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Solvent: C1CCOC1
Product: Cc1c(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3ccc(N4CCN(C)CC4)cc3)c2)cnn1C
Temperature: 65 °C
Reaction time: 24 h
Yield: 11 %

Procedure:
A small screw cap test tube was charged with 1,5-Dimethyl-1H-pyrazole-4-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (prepared below, 134 mg, 0.333 mmol) and THF (3.3 mL). To the resulting solution was added 4-(4-methyl-piperazin-1-yl)-phenylamine (64.2 mg, 0.336 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was dissolved in EtOAc (˜5 mL) and the resulting solution was triturated with Hexanes (˜40 mL). The precipitate that formed was collected by filtration and washed with 0° C. iPrOH (˜10 mL) to afford the title compound in 11% yield (0.021 g, 0.036 mmol).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([CH2:11][CH3:12])[N:7]([CH2:13][C:14]([OH:16])=O)[C:6]=2[CH:5]=[CH:4][C:3]=1[C:17]#[N:18].[F:19][C:20]([F:32])([F:31])[C:21]1[N:26]=[CH:25][C:24]([C:27]([NH:29][NH2:30])=O)=[CH:23][CH:22]=1>>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]([CH2:11][CH3:12])[N:7]([CH2:13][C:14]3[O:16][C:27]([C:24]4[CH:25]=[N:26][C:21]([C:20]([F:32])([F:19])[F:31])=[CH:22][CH:23]=4)=[N:29][N:30]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[C:17]#[N:18]
Reactant: NNC(=O)c1ccc(C(F)(F)F)nc1
Reactant: CCc1nc2c(Cl)c(C#N)ccc2n1CC(=O)O
Product: CCc1nc2c(Cl)c(C#N)ccc2n1Cc1nnc(-c2ccc(C(F)(F)F)nc2)o1

Procedure:
Synthesized as described in Example 200C from (4-chloro-5-cyano-2-ethyl-1H-benzimidazol-1-yl)acetic acid and 6-(trifluoromethyl)-3-pyridinecarbohydrazide: MS (APCl) m/z 433 (M+1).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][CH:3]=1.[OH-].[Na+].[S:12]1(=[O:18])(=[O:17])[CH2:16][CH2:15][CH2:14][NH:13]1>O>[N:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:13]2[CH2:14][CH2:15][CH2:16][S:12]2(=[O:18])=[O:17])=[CH:4][CH:3]=1
Reactant: ClCc1ccncc1
Reactant: O=S1(=O)CCCN1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=S1(=O)CCCN1Cc1ccncc1
Reaction time: 2 h

Procedure:
A mixture of 4-picolylchloride hydrochloride (2.7 g) was stirred in water (10 cm3) with sodium hydroxide (1.3 g) during the addition of isothiazolidine-1,1-dioxide (2.0 g) in water (5 cm3). After stirring for 2 hours the mixture was extracted with chloroform (3×15 cm3) and the dried (MgSO4) extracts were evaporated in vacuo to give an oil which was chromatographed on silica (MK 60. 9385) eluting with ethyl acetate to give an oil which crystallised from ethyl acetate affording 2-(4-pyridylmethyl)isothiazolidine-1,1-dioxide as white crystals, m.p. 82° (3.5 g).
Reaction SMILES: [OH:1]/[N:2]=[C:3](\[NH2:17])/[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:6][CH:5]=1.CN(C)N1C=CC=CC1.[CH2:27]([O:34][C:35]1[CH:43]=[CH:42][C:38]([C:39](Cl)=O)=[CH:37][CH:36]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>N1C=CC=CC=1>[CH2:27]([O:34][C:35]1[CH:36]=[CH:37][C:38]([C:39]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[CH:6][C:7]([O:10][C:11]4[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=4)=[CH:8][CH:9]=3)[N:17]=2)=[CH:42][CH:43]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: N/C(=N\O)c1ccc(Oc2cccnc2)cc1
Reactant: O=C(Cl)c1ccc(OCc2ccccc2)cc1
Agent: CN(C)N1C=CC=CC1
Solvent: c1ccncc1
Product: c1ccc(COc2ccc(-c3nc(-c4ccc(Oc5cccnc5)cc4)no3)cc2)cc1
Temperature: 25 °C
Yield: 79.2 %

Procedure:
(Z)-N′-Hydroxy-4-(pyridin-3-yloxy)benzamidine (206 mg, 89.9 μmol), N-dimethylaminopyridine (1.1 mg, 9.0 μmol) and 4-benzyloxybenzoyl chloride (28.8 mg, 116.8 μmol) were suspended in pyridine (5.0 mL) and the solution was refluxed for 45 hours. The reaction mixture was then cooled to room temperature, the solvent was removed under reduced pressure and the solid residue was purified by column chromatography (EtOAc/Hex 1:4) to give the product as a white solid (30 mg, 78%). 1H NMR (500 MHz, CDCL3) δ(ppm): 5.16 (2H, s), 7.11 (2H, d, J=6.0 Hz), 7.12 (2H, d, J=6.2 Hz), 7.33-7.37 (2H, m), 7.39-7.46 (5H, m), 8.15 (2H, d, J=7.6 Hz), 8.17 (2H, d, J=7.4 Hz), 8.45 (1H, d, J=4.6 Hz), 8.49 (1H, d, J=2.4 Hz). 13C NMR (125 MHz, CDCL3) δ(ppm): 70.4 (CH2), 115.5 (CH), 117.2, 118.8 (CH), 123.0 (CH), 124.6, 126.8 (CH), 127.7 (CH), 128.5 (CH), 128.8, 128.9 (CH), 129.7 (CH), 130.3 (CH), 136.2, 141.9, 145.0, 159.1, 162.5, 168.3, 175.8. MS (FAB+): 422 (MH+). HRMS for C26H19N3O3 (MH+): calculated: 422.1505; found 422.1521.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:17]([F:19])[F:18])[N:6]2[CH2:13][C:14]([OH:16])=O.CCN=C=NCCCN(C)C.Cl.O[NH:33][C:34]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1)=[NH:35]>ClCCCl>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:17]([F:19])[F:18])[N:6]2[CH2:13][C:14]1[O:16][N:35]=[C:34]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=2)[N:33]=1
Reactant: N#Cc1ccc2c(cc(C(F)F)n2CC(=O)O)c1Cl
Reactant: N=C(NO)c1ccccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCCl
Product: N#Cc1ccc2c(cc(C(F)F)n2Cc2nc(-c3ccccn3)no2)c1Cl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 59.3 %

Procedure:
To a suspension of [4-chloro-5-cyano-2-(difluoromethyl)-1H-indol-1-yl]acetic acid (0.020 g, 0.070 mmol) in DCE (2 mL), under N2 was added EDCl (0.015 g, 0.077 mmol) and the resulting mixture was stirred at rt. After 5 min, N-hydroxy-2-pyridinecarboximidamide (0.011 g, 0.077 mmol) was added. After stirring at rt for 30 min, the mixture was heated in a microwave at 150° C. for 20 min. Upon cooling, the mixture was partitioned between EtOAc and 0.1N HCl. The organic phase was washed with sat'd NaHCO3 solution and brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography (0-100% EtOAc-hexanes gradient) and the product was crystallized from CH2Cl2-MeOH-hexanes to give the title compound as a white solid (0.016 g, 59% yield): MS (ES) m/z 386 (M+1).
Reaction SMILES: [CH2:1]([N:5]([C:15]1[N:16]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[N:17]=[C:18]2[C:23]=1[CH:22]=[CH:21][CH:20]=[CH:19]2)C(NC1CCCCC1)=O)[CH2:2]CC.[CH3:31][O:32]CCN>CN1CCCC1=O>[Cl:30][C:27]1[CH:26]=[CH:25][C:24]([N:16]2[C:15]([NH:5][CH2:1][CH2:2][O:32][CH3:31])=[C:23]3[C:18]([CH:19]=[CH:20][CH:21]=[CH:22]3)=[N:17]2)=[CH:29][CH:28]=1
Reactant: COCCN
Reactant: CCCCN(C(=O)NC1CCCCC1)c1c2ccccc2nn1-c1ccc(Cl)cc1
Solvent: CN1CCCC1=O
Product: COCCNc1c2ccccc2nn1-c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described in example 4.1, 3-chloro-2-(4-chloro-phenyl)-2H-indazole (Ardakani, Manouchehr; Smalley, Robert K.; Smith, Richard H., Synthesis (1979), (4), 308-9) was reacted with 2-methoxy-ethylamine ([109-85-3]) in N-methyl 2-pyrrolidone for 48 h at 175° C. in a sealed tube to give the title compound as yellow oil. MS: m/e=302.3 [M+H+].
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[C:28]([N:32]([CH2:40][CH2:41][CH2:42][N:43]([CH3:45])[CH3:44])[C:33]1[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=1)(=[O:31])[CH2:29][CH3:30]>>[C:28]([N:32]([C:33]1[CH:38]=[CH:37][C:36]([NH:39]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=3)/[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:35][CH:34]=1)[CH2:40][CH2:41][CH2:42][N:43]([CH3:44])[CH3:45])(=[O:31])[CH2:29][CH3:30]
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(OC)c(OC)cc21)c1ccccc1
Reactant: CCC(=O)N(CCCN(C)C)c1ccc(N)cc1
Product: CCC(=O)N(CCCN(C)C)c1ccc(N/C(=C2\C(=O)Nc3cc(OC)c(OC)cc32)c2ccccc2)cc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone and N-propionyl-N-(3-dimethylamino-propyl)-p-phenylenediamine
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[C:8]([OH:11])=[CH:9][CH:10]=1)=[O:4].[Br:22][CH2:23][CH2:24][CH2:25]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:14][CH:13]=2)[C:8]([O:11][CH2:25][CH2:24][CH2:23][Br:22])=[CH:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1ccc(O)c(-c2ccc(C(F)(F)F)cc2)c1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OCCCBr)c(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Yield: 72.8 %

Procedure:
To a solution of 6-hydroxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid methyl ester (1.20 g, 4.05 mmol) and 1,3-dibromopropane (4.09 g, 20.3 mmol) in acetone (125 mL) was added potassium carbonate (2.80 g, 20.3 mmol). The reaction mixture was heated to reflux for 3 hours and allowed to cool back down to room temperature. The mixture was partitioned between ethyl acetate and brine, and the layers were separated. The aqueous layer was extracted with one additional portion of ethyl acetate. The organics were combined, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude oil was purified by flash chromatography through silica gel using ethyl acetate/hexanes (0/100 gradient to 9/91) to give 6-(3-bromo-propoxy)-4′-trifluoromethyl-biphenyl-3-carboxylic acid methyl ester (1.23 g, 73%) as a white powder. 1H NMR (400 MHz, CDCl3); δ 8.03 (d, 1H), 7.99 (s, 1H), 7.61 (AA′BB′, 4H), 7.02 (d, 1H), 4.18 (t, 2H), 3.88 (s, 3H), 3.43 (t, 2H), 2.23 (m, 2H).
Reaction SMILES: C[Mg]Br.[CH2:4](OCC)C.[CH3:9][O:10][C:11]1[CH:26]=[CH:25][C:14]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=O)=[CH:13][CH:12]=1>C(OCC)C>[CH3:9][O:10][C:11]1[CH:26]=[CH:25][C:14]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[CH2:4])=[CH:13][CH:12]=1
Reactant: CCOCC
Reactant: COc1ccc(C(=O)c2ccc(OC)cc2)cc1
Agent: C[Mg]Br
Product: C=C(c1ccc(OC)cc1)c1ccc(OC)cc1

Procedure:
An equivalent of methyl magnesium bromide/diethyl ether solution is reacted with 4,4′-dimethoxybenzophenone (24.2 g, 0.1 mol) dissolved in anhydrous diethyl ether over a 60 minute period at ambient temperature. The reaction mixture is poured onto ice and extracted with ether. The ether is removed by distillation and replaced with ethyl acetate (100 mL). The ethyl acetate solution is refluxed for one hour over anhydrous magnesium sulfate. Methylene chloride (300 mL) is added and the magnesium sulfate removed by filtration. The solvent is distilled leaving 16.9 g of the title compound as a white solid melting at 137° C. whose structure is consistent with 1Hnmr and mass spectrometry.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:4][C:3]=1[NH:17][C@@H:18]1[CH2:23][CH2:22][C@H:21]([C:24]([NH:26][CH:27]([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1.[F:30][C:31]1[CH:65]=[CH:64][C:34]([C:35](/[N:37]=[C:38]2/N([C@H]3CC[C@@H](C(=O)NC(C)C)CC3)C3C=C(OCCOC)N=CC=3N/2)=[O:36])=[CH:33][CH:32]=1>>[F:30][C:31]1[CH:32]=[CH:33][C:34]([C:35](/[N:37]=[C:38]2\[NH:1][C:2]3[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][N:11]4[CH2:16][CH2:15][O:14][CH2:13][CH2:12]4)=[CH:4][C:3]=3[N:17]\2[C@H:18]2[CH2:23][CH2:22][C@@H:21]([C:24](=[O:25])[NH:26][CH:27]([CH3:29])[CH3:28])[CH2:20][CH2:19]2)=[O:36])=[CH:64][CH:65]=1
Reactant: COCCOc1cc2c(cn1)[nH]/c(=N\C(=O)c1ccc(F)cc1)n2[C@H]1CC[C@@H](C(=O)NC(C)C)CC1
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](Nc2cc(OCCN3CCOCC3)ccc2N)CC1
Product: CC(C)NC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)cc3)[nH]c3ccc(OCCN4CCOCC4)cc32)CC1

Procedure:
The title compound was prepared from cis-4-(2-amino-5-(2-morpholinoethoxy)phenylamino)-N-isopropylcyclohexanecarboxamide using a procedure analogous to that used for (E)-4-fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-methoxyethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide. Isolated as an off-white solid (19 mg, 35% yield). M/Z calc'd for C30H38FN5O4: 551.65. found 552 [M+H].
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][CH2:23][CH2:24][OH:25])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:26])[CH3:9])=[CH:4][CH:3]=1.[CH3:27][C:28]1[N:33]=[C:32](B(O)O)[CH:31]=[CH:30][CH:29]=1>>[OH:25][CH2:24][CH2:23][CH2:22][C@@:13]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:12][C:11](=[O:26])[N:10]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:32]3[CH:31]=[CH:30][CH:29]=[C:28]([CH3:27])[N:33]=3)=[CH:3][CH:4]=2)[CH3:9])[CH2:15][CH2:14]1
Reactant: Cc1cccc(B(O)O)n1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCO)(c2ccccc2)OC1=O
Product: Cc1cccc(-c2ccc([C@H](C)N3CC[C@](CCCO)(c4ccccc4)OC3=O)cc2)n1

Procedure:
The title compound was prepared from (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one and 6-methylpyridine-2-boronic acid following procedures analogous to those described in Example 75 Step 1. LC-MS Method 2 tR=0.986 min, m/z=431.1; 1H NMR (CDCl3) 1.33 (m, 2H), 1.52 (d, 3H), 1.69 (m, 1H), 1.97 (m, 2H), 2.12-2.30 (m, 3H), 2.56 (s, 3H), 2.85 (m, 1H), 3.52 (t, 2H), 5.67 (m, 1H), 6.95 (d, 2H), 7.03 (d, 1H), 7.22-7.37 (m, 6H), 7.55 (t, 1H), 7.64 (d, 2H).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.CS(O[CH2:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[CH:35]=[O:36])(=O)=O>CN(C)C=O>[C:42]1([CH2:41][O:40][C:39]2[CH:38]=[CH:37][C:34]([CH:35]=[O:36])=[CH:33][C:32]=2[CH2:31][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: c1ccc(CCNCc2ccccc2)cc1
Reactant: CS(=O)(=O)OCc1cc(C=O)ccc1OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCc2ccccc2)c(CN(CCc2ccccc2)Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87 %

Procedure:
To a solution of N-benzyl-N-(2-phenylethyl)amine (351 mg) and diisopropyl-ethylamine (145 mg) in dimethylformamide (1.5 ml) was added 3-[[(methylsulfonyl)oxy]methyl]-4-phenylmethoxybenzaldehyde (355 mg). After stirring at room temperature for 3 hours, the reaction mixture was partially concentrated under reduced pressure and the residue was purified by flash chromatography column using petroleum ether:diethyl ether (1:3) as eluant. The pure fractions were combined and evaporated under reduced pressure to give 4-phenylmethoxy-3-[[N-phenylmethyl-N-(2-phenylethyl)amino]methyl]benzaldehyde (420 mg) as a gum. 1H NMR (CDCl3) δ9.89 (s, 1H, CHO); 5.20 (s, 2H); 3.88 (s, 2H); 3.85 (s, 2H); 2.92 (m, 4H, CH2CH2).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.[F:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1.O>S(Cl)(Cl)=O.C(OCC)C>[F:11][C:12]1[CH:18]=[CH:17][C:15]([NH:16][C:8]([C:6]2[N:7]=[C:2]([Cl:1])[CH:3]=[CH:4][CH:5]=2)=[O:10])=[CH:14][CH:13]=1
Reactant: O=C(O)c1cccc(Cl)n1
Reactant: Nc1ccc(F)cc1
Solvent: CCOCC
Solvent: O
Solvent: O=S(Cl)Cl
Product: O=C(Nc1ccc(F)cc1)c1cccc(Cl)n1
Yield: 81 %

Procedure:
6-chloropicolinic acid (51.2 g, 0.325 mol) in thionyl chloride (90 ml) was stirred and heated to reflux for 2 hours. The excess thionyl chloride was evaporated in vacuo and diethylether (250 ml) added to the residual 6-chloropicolinoyl chloride. A solution of 4-fluoroaniline (37.5 g, 0.338 mol) in diethylether (100 ml) was added with stirring, maintaining the temperature below 20° C. After the addition, the reaction mixture was stirred overnight at ambient temperature. Water was added to the reaction mixture and the organic layer separated. After a further washing with water and drying with anhydrous magnesium sulphate, the solvent was removed in vacuo to give the title compound as a pale brown solid (66 g, 82%), mp 98° C.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1([F:29])[C:12](=[O:13])[C:11]2[N:7]([C:8]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)=[C:9]3[C:17](=[O:18])[N:16]([CH3:19])[C:15](=[O:20])[N:14]([CH3:21])[C:10]3=2)[CH2:6][CH2:5]1>CO.O1CCCC1>[F:29][C:4]1([F:3])[CH:12]([OH:13])[C:11]2[N:7]([C:8]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)=[C:9]3[C:17](=[O:18])[N:16]([CH3:19])[C:15](=[O:20])[N:14]([CH3:21])[C:10]3=2)[CH2:6][CH2:5]1
Reactant: Cn1c(=O)c2c(-c3cccc(F)c3)n3c(c2n(C)c1=O)C(=O)C(F)(F)CC3
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Cn1c(=O)c2c(-c3cccc(F)c3)n3c(c2n(C)c1=O)C(O)C(F)(F)CC3
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium borohydride (7.2 mg, 0.19 mmol) was added to solution of 9,9-difluoro-5-(3-fluorophenyl)-1,3-dimethyl-8,9-dihydropyrimido[4,5-a]indolizine-2,4,10(1H,3H,7H)-trione (55 mg, 0.15 mmol) in methanol (1 mL) and tetrahydrofuran (1 mL) at 0° C. The mixture was stirred at room temperature for 30 mins. The reaction was quenched with water (10 mL) and extracted with DCM (6×5 mL). The combined organic extracts were passed through a hydrophobic frit and evaporated under vacuum to afford the title compound.
Reaction SMILES: [Na].S(NN=[CH:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)(C1C=CC(C)=CC=1)(=O)=O.[CH:22]([N:24]1[C:28](=[O:29])[C:27]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]2[C:25]1=[O:34])=[CH2:23].O>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.O1CCOCC1.C([O-])(=O)C.[Rh+3].C([O-])(=O)C.C([O-])(=O)C>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([CH:14]2[CH2:23][CH:22]2[N:24]2[C:25](=[O:34])[C:26]3[C:27](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28]2=[O:29])=[CH:20][CH:19]=1
Reactant: Cc1ccc(S(=O)(=O)NN=Cc2ccc(Cl)cc2)cc1
Reactant: C=CN1C(=O)c2ccccc2C1=O
Agent: [Rh+3]
Agent: CC(=O)[O-]
Agent: CC[N+](CC)(CC)Cc1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: O=C1c2ccccc2C(=O)N1C1CC1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 26.1 %

Procedure:
A mixture of 4-chlorobenzaldehyde tosyl hydrazone sodium salt (1.67 g, 5.05 mmol), benzyltriethylammoniumchloride (115 mg, 0.5 mmol), rhodium acetate (20 mg, 0.05 mmol) and N-vinylphtalimide (4.32 g, 25.0 mmol) in dry 1,4-dioxane (13 ml) was stirred for one day under nitrogen at room temperature. Water (35 ml) was added to the mixture and the aqueous phase was extracted three times with dichloromethane. The combined organic layers were dried over Na2SO4. Evaporation gave the crude material, which was purified by flash chromatography over silicagel (eluent: hexane/ethylacetate 1:1). To afford 392 mg (26.3% of theory) of 2-[2-(4-chloro-phenyl)-cyclopropyl]-isoindole-1,3-dione in the form of a solid.