Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([CH2:9]P(=O)(OCC)OCC)#[N:8].[CH:18]([C:20]1([C:23]#[N:24])[CH2:22][CH2:21]1)=O>C1COCC1>[C:7](/[CH:9]=[CH:18]/[C:20]1([C:23]#[N:24])[CH2:22][CH2:21]1)#[N:8]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: N#CC1(C=O)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#C/C=C/C1(C#N)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 19.2 %

Procedure:
To a solution of 1.0 M potassium tert-butoxide in THF (1.12 mL) at 0° C. was added slowly dropwise a solution of diethyl cyanomethylphosphonate (210 mg, 1.2 mmol) in THF (2 mL). The cold bath was removed and the reaction was warmed to ambient temperature. The solution was then re-cooled to 0° C. and a solution of 1-formylcyclopropanecarbonitrile (101 mg, 1.06 mmol) in THF (1.0 mL) was added dropwise. The cold bath was removed and the reaction was stirred for 3 hours at ambient temperature. The mixture was then diluted with ether and water, the ether solution was separated, washed with brine, dried over sodium sulfate, filtered and the solvent was removed in vacuo. Flash column chromatography (eluting with a gradient from 0-60% ethyl ether in hexanes) afforded the product (24 mg, 19%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[C:5]([I:9])=[CH:4][C:3]=1[Cl:10].[OH:11][C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=1.C([O-])([O-])=O.[Na+].[Na+].O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:10][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([C:16]2[CH:17]=[C:12]([OH:11])[CH:13]=[CH:14][CH:15]=2)=[C:5]([I:9])[CH:4]=1
Reactant: Clc1cc(I)c(I)cc1Cl
Reactant: OB(O)c1cccc(O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Oc1cccc(-c2cc(Cl)c(Cl)cc2I)c1
Temperature: 25 °C
Yield: 21.9 %

Procedure:
A mixture of 1,2-dichloro-4,5-diiodobenzene (1.5 g, 3.76 mmol), 3-hydroxyphenylboronic acid (0.52 g, 3.76 mmol), Na2CO3 (1.99 g, 18.8 mmol) and Pd(PPh3)4 (0.35 g, 0.30 mmol), in 1,4-dioxane (10 mL) and water (2 mL) was stirred at reflux under argon for 16 h. The mixture was allowed to cool to room temperature and then concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate=20:1) to afford the desired product (300 mg, 22% yield). ESI-MS m/z: 362.9 [M−H]−.
Reaction SMILES: [CH:1]1([NH:5][C:6](=[O:27])[C:7]2[CH:12]=[C:11]([O:13][C:14]3[C:19]([CH3:20])=[CH:18][C:17]([N+:21]([O-:23])=[O:22])=[CH:16][C:15]=3[CH3:24])[CH:10]=[CH:9][C:8]=2[O:25][CH3:26])[CH2:4][CH2:3][CH2:2]1.[H-].[Na+].I[CH3:31].O>CN(C)C=O>[CH:1]1([N:5]([CH3:31])[C:6](=[O:27])[C:7]2[CH:12]=[C:11]([O:13][C:14]3[C:19]([CH3:20])=[CH:18][C:17]([N+:21]([O-:23])=[O:22])=[CH:16][C:15]=3[CH3:24])[CH:10]=[CH:9][C:8]=2[O:25][CH3:26])[CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(Oc2c(C)cc([N+](=O)[O-])cc2C)cc1C(=O)NC1CCC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Oc2c(C)cc([N+](=O)[O-])cc2C)cc1C(=O)N(C)C1CCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95.2 %

Procedure:
To a solution of N-Cyclobutyl-5-(2,6-dimethyl-4-nitro-phenoxy)-2-methoxy-benzamide (1.67 grams, 4.51 mmol) in N,N-dimethylformamide (50 mL) at 0° C. under nitrogen was added NaH (60% dispersion in mineral oil, 0.27 grams, 11 mmol). After stirring 30 minutes at 0° C., iodomethane (3.2 g, 23 mmol) was added at 0° C. The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 16 hours, poured into water (450 mL), and extracted with ethyl acetate (3 times 75 mL). The combined organic extracts were washed with water (5 times 200 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (20% ethyl acetate in hexane to 40% ethyl acetate in hexane) to afford the title compound (1.65 grams) as an off white foam. 1H NMR (400 MHz, CDCl3) δ7.96 (s, 2H), 6.80-6.52 (m, 3H, 2 rotomers observed), 5.04, 4.02-3.98 (m, m, 1H, 2 rotomers observed), 3.74, 3.67 (s,s, 3H, 2 rotomers observed), 3.02, 2.75 (s,s, 3H, 2 rotomers observed), 2.25-1.94 (m, 9H, 2 rotomers observed), 1.75-1.41 (m, 3H, 2 rotomers observed). MS (APCI+) Calc: 384.0, Found: 385.2 (M+1).
Reaction SMILES: [C:1]1([C@H:11]([NH:13][CH2:14][C@@H:15]2[C@@H:19]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)[CH2:18][N:17]([C:30](=[O:45])[CH2:31][CH2:32][CH2:33][CH2:34][C:35]([O:37]CC3C=CC=CC=3)=[O:36])[CH2:16]2)[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO.C1COCC1>[C:1]1([C@H:11]([NH:13][CH2:14][C@@H:15]2[C@@H:19]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:27])[F:28])[CH:21]=3)[CH2:18][N:17]([C:30](=[O:45])[CH2:31][CH2:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36])[CH2:16]2)[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: C[C@@H](NC[C@H]1CN(C(=O)CCCCC(=O)OCc2ccccc2)C[C@@H]1c1cccc(C(F)(F)F)c1)c1cccc2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@@H](NC[C@H]1CN(C(=O)CCCCC(=O)O)C[C@@H]1c1cccc(C(F)(F)F)c1)c1cccc2ccccc12
Reaction time: 16 h

Procedure:
A 310 mg portion of benzyl 6-{(3S,4S)-3-({[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-[3-(trifluoromethyl)phenyl]pyrrolidin-1-yl}-6-oxohexanoate was dissolved in 2 ml of methanol and 2 ml of THF, mixed with 2 ml of 1 M sodium hydroxide aqueous solution at room temperature and stirred for 16 hours. The reaction solution was washed with diethyl ether, 1 M hydrochloric acid was added to the water layer until its pH became 2.0, and then this was extracted with chloroform. After washing this with saturated brine, the organic layer was dried with anhydrous sodium sulfate and concentrated under a reduced pressure. By purifying the thus obtained residue by a silica gel column chromatography (chloroform-methanol), 6-{(3S,4S)-3-({[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-[3-(trifluoromethyl)phenyl]pyrrolidin-1-yl}-6-oxohexanoic acid was obtained. The thus obtained compound was dissolved in 2 ml of 4 M hydrogen chloride/1,4-dioxane solution and then concentrated under a reduced pressure. THF and diethyl ether were added to the residue, the thus obtained precipitate was collected by filtration, and the filtered product was dried under a reduced pressure to obtain 200 mg of 6-{(3S,4S)-3-({[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-[3-(trifluoromethyl)phenyl]pyrrolidin-1-yl}-6-oxohexanoic acid hydrochloride as a colorless solid.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[C:16]([F:27])[C:17]3[C:21]([NH2:22])=[C:20]([C:23](=[O:25])[NH2:24])[S:19][C:18]=3[CH:26]=2)[CH2:10][CH2:9]1)(C)(C)C.Cl>C(Cl)Cl.O1CCOCC1>[NH2:22][C:21]1[C:17]2[C:16]([F:27])=[CH:15][C:14]([N:11]3[CH2:10][CH2:9][CH:8]([NH2:7])[CH2:13][CH2:12]3)=[CH:26][C:18]=2[S:19][C:20]=1[C:23]([NH2:24])=[O:25]
Reactant: CC(C)(C)OC(=O)NC1CCN(c2cc(F)c3c(N)c(C(N)=O)sc3c2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: NC(=O)c1sc2cc(N3CCC(N)CC3)cc(F)c2c1N
Temperature: 25 °C
Reaction time: 72 h
Yield: 23.2 %

Procedure:
To a solution of 0.055 g (0.14 mmol) of [1-(3-amino-2-carbamoyl-4-fluoro-benzo[b]thiophen-6-yl)-piperidin-4-yl]-carbamic acid tert-butyl ester in CH2Cl2 (1 mL) was added 0.07 mL (0.3 mmol) of a 4.0 M solution of HCl in 1,4-dioxane. The mixture was stirred at room temperature for 3 days during which time a solid precipitated from solution. The solid was collected by filtration and washed with CH2Cl2. The material was purified by reverse phase HPLC to provide 0.010 g (18%) of the title compound as a white solid. MS calc. for C14H17FN4OS [M+H]+: 309.38. Found: 309.26.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH:5]([C:7]1[CH:8]=[C:9]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=2[CH:25]=O)[C:10]([O:13][CH3:14])=[CH:11][CH:12]=1)[CH3:6])[CH3:2].[CH2:28]([NH2:30])[CH3:29]>>[CH2:1]([O:3][C:4](=[O:27])[CH:5]([C:7]1[CH:8]=[C:9]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:17][C:16]=2[CH2:25][NH:30][CH2:28][CH3:29])[C:10]([O:13][CH3:14])=[CH:11][CH:12]=1)[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)c1ccc(OC)c(-c2ccc(C(F)(F)F)cc2C=O)c1
Reactant: CCN
Product: CCNCc1cc(C(F)(F)F)ccc1-c1cc(C(C)C(=O)OCC)ccc1OC

Procedure:
Prepared according to the procedure described in Example 1, Step 5, using the following starting materials: 2-(2′-formyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-propionic acid ethyl ester and ethylamine (2M in THF).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:27][CH2:26][NH:25][C:24]3=[O:28])=[CH:19][CH:18]=2)=[O:16])[CH2:11][CH2:10]1.[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:29]([N:25]1[CH2:26][CH2:27][N:23]([C:20]2[CH:21]=[CH:22][C:17]([C:15]([N:12]3[CH2:13][CH2:14][N:9]([C:3]4[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=4[CH3:1])[CH2:10][CH2:11]3)=[O:16])=[CH:18][CH:19]=2)[C:24]1=[O:28])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: BrCc1ccccc1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCNC4=O)cc3)CC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCN(Cc5ccccc5)C4=O)cc3)CC2)c(C)c1

Procedure:
Using 1-{4-[4-(2,4-dimethylphenyl)piperazine-1-carbonyl]phenyl}imidazolidin-2-one (100 mg) described in Example 401 and benzyl bromide (35 μL) and by the reaction and treatment in the same manner as in Example 36, the title compound (63 mg) was obtained.
Reaction SMILES: [CH3:1][Si:2]([CH3:23])([CH3:22])[CH2:3][CH2:4][O:5][C:6](=[O:21])[N:7]([CH2:9][C@@H:10]([N:18]=[C:19]=[S:20])[CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[CH3:8].[N:24]#[C:25][NH2:26].[Na]>C(O)C.[NH4+].[Cl-].O>[C:25]([NH:26][C:19]([NH:18][C@@H:10]([CH2:11][CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1)[CH2:9][N:7]([CH3:8])[C:6]([O:5][CH2:4][CH2:3][Si:2]([CH3:1])([CH3:22])[CH3:23])=[O:21])=[S:20])#[N:24]
Reactant: N#CN
Reactant: CN(C[C@H](CC1CCCCC1)N=C=S)C(=O)OCC[Si](C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CN(C[C@H](CC1CCCCC1)NC(=S)NC#N)C(=O)OCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 108.9 %

Procedure:
To a stirred solution of (2-(trimethylsilyl)ethyl)(S)-3-cyclohexyl-2-isothiocyanatopropyl-methylcarbamate (190 mg, 0.53 mmol) in ethanol (5 mL) was added solid sodium hydrogen cyanamide (38 mg, 0.59 mmol). The mixture was stirred at rt for 2 d, diluted with 1:1 sat'd aq NH4Cl/H2O (40 mL) and extracted with ether (2×60 mL). The combined ether extracts were dried over MgSO4 and rotovaped to leave 1-cyano-3-((S)-3-cyclohexyl-1-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propan-2-yl)thiourea (230 mg, quant) as a white solid.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].[F:20][C:21]([F:28])([F:27])[CH2:22][CH2:23][C:24](O)=[O:25]>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:19])[N:2]([NH:1][C:24](=[O:25])[CH2:23][CH2:22][C:21]([F:28])([F:27])[F:20])[N:11]=2)=[CH:13][CH:14]=1
Reactant: O=C(O)CCC(F)(F)F
Reactant: Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O
Product: O=C(CCC(F)(F)F)Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O

Procedure:
The product from Example 86A and 4,4,4-trifluorobutanoic acid were treated using a method similar to that described in Example 57 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.40-8.43 (m, 1H), 7.89-8.05 (m, 2H), 7.73-7.75 (m, 1H), 7.60-7.70 (m, 4H), 2.58-2.71 (m, 4H); MS (ESI−) M/Z 394 (M−H)−.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[N:12]=[CH:13][N:14]=[C:7]1[CH:6]=[CH:5]2.[SH:15][C:16]1[CH:17]=[C:18]([C:22]2([C:28]#[N:29])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:19]=[CH:20][CH:21]=1.CCN(C(C)C)C(C)C.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N:12]1[N:8]2[C:9]3[C:4]([CH:5]=[CH:6][C:7]2=[N:14][CH:13]=1)=[CH:3][C:2]([S:15][C:16]1[CH:17]=[C:18]([C:22]2([C:28]#[N:29])[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)[CH:19]=[CH:20][CH:21]=1)=[CH:11][CH:10]=3
Reactant: N#CC1(c2cccc(S)c2)CCOCC1
Reactant: Brc1ccc2c(ccc3ncnn32)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: N#CC1(c2cccc(Sc3ccc4c(ccc5ncnn54)c3)c2)CCOCC1
Temperature: 110 °C

Procedure:
8b (66 mg, 0.25 mmol) and 4-(3-Mercapto-phenyl)-tetrahydro-pyran-4-carbonitrile (8c, 90 mg, 0.32 mmol) were dissolved in 1,4-dioxane (5 mL) and degassed for 10 minutes with N2. iPr2NEt (0.15 mL, 0.80 mmol) was added, followed by Pd2dba3 (10 mg, 0.01 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (12 mg, 0.02 mmol), and the mixture was degassed with N2 for an additional 10 minutes. The reaction was sealed and heated overnight at 110° C. Additional catalyst was added after 24 hours to push the reaction to completion, and the mixture was heated at 110° C. for another 2 hours. The reaction was cooled to room temperature and purified by silica gel chromatography (25-100% EtOAc in hexanes) to give the desired product, 8d.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[I:21].[C:22](Cl)(=[O:24])[CH3:23]>N1C=CC=CC=1>[C:22]([NH:1][C:2]1[N:6]([C:7]2[C:8]([Cl:18])=[CH:9][C:10]([C:14]([F:17])([F:15])[F:16])=[CH:11][C:12]=2[Cl:13])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[I:21])(=[O:24])[CH3:23]
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1I
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Product: CC(=O)Nc1c(I)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a stirred solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-iodopyrazole (447 mg, the compound of Example A1) in pyridine (5ml) was added dropwise acetyl chloride (0.5 ml). The reaction mixture was stirred at room temperature for 2 days and then heated at 50° C. for 4 hours. The reaction mixture was partitioned between ether (50 ml) and water (50ml), the organic layer was separated, dried (MgSO4) and evaporated.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]([C:11]=1Br)[CH2:9][CH2:8][C:7]1[CH:13]=[CH:14][CH:15]=[CH:16][C:6]=1[C:5]2=[O:17].C(O)C.[H][H]>[Pd].C(N(CC)CC)C>[CH:3]1[CH:2]=[CH:11][N:10]2[CH2:9][CH2:8][C:7]3[CH:13]=[CH:14][CH:15]=[CH:16][C:6]=3[C:5](=[O:17])[C:4]=12
Reactant: O=C1c2ccccc2CCn2c1cc(Br)c2Br
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2CCn2cccc21

Procedure:
A suspension of 25 g. (0.070 mole) of 2,3-dibromo-6,11-dihydro-5 H-pyrrolo[2,1-b][3]benzazepin-11-one in 200 ml. ethanol containing 25 ml. of triethylamine and 1 gm. of 10% Pd on charcoal was hydrogenated under 3 atmospheres of hydrogen to yield 6,11-dihydro-5H-pyrrolo-[2,1-b][3]benzazepin-11-one, m.p. 54°-55° C. after removal of catalyst, recrystallization from petroleum ether and drying under vacuum. The same compound is also obtained by hydrogenolysis of the 2,3-dichloro ketone and the 1,2,3-tribromoketone.
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:24][C:25]4[CH:26]=[N:27][C:28]([O:32][CH3:33])=[C:29]([F:31])[CH:30]=4)=[N:18][CH:19]=[C:20]([CH:23]=3)[CH:21]=[O:22])[N:10]=2)=CC=1.C(O)(C(F)(F)F)=O.S(O)(C(F)(F)F)(=O)=O>C(Cl)Cl>[NH2:8][C:9]1[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]2[C:17]([NH:24][C:25]3[CH:26]=[N:27][C:28]([O:32][CH3:33])=[C:29]([F:31])[CH:30]=3)=[N:18][CH:19]=[C:20]([CH:23]=2)[CH:21]=[O:22])[N:10]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C=O)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ncc(Nc2ncc(C=O)cc2-c2nc(C)nc(N)n2)cc1F
Temperature: 80 °C
Reaction time: 2.5 h

Procedure:
A solution of 5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)nicotinaldehyde (380 mg, 0.638 mmol) in DCM (5 mL) was treated with TFA (6.0 mL, 78 mmol) and then TfOH (0.050 mL, 0.563 mmol). The solution was heated at 80° C. under a condenser. After 2.5 h, more TfOH (0.050 mL, 0.563 mmol) was added. After 24 h, the mixture was concentrated. The residue was azeotroped with toluene (10 mL) once. The mixture was suspended in 1:1 DMSO-water (5 mL each) and filtered. The resulting solid was then suspended in saturated NaHCO3 for several hours and filtered. The mother liquor was discarded. The resulting sludge was dissolved in hot DMSO and filtered. The filtrate was diluted with MeOH (2× v/v) and allowed to settle. The resulting suspension was filtered. The resulting solid was again dissolved in hot DMSO and diluted with MeOH. After 3 repetitions, the solid was about 95% pure product (50 mg). LCMS (ES, pos.): calcd for C16H14FN7O2: 355.1. found: 356.2 (M+H)+. 1H NMR (400 MHz, d6-DMSO) δ 12.47 (br. s., 1H); 9.92 (s, 1H); 9.17 (br. s., 1H); 8.81 (br. s., 1H); 8.42 (br. s., 1H); 8.32 (d, J=13.11 Hz, 1H); 8.01 (br. s., 1H); 7.85 (d, J=0.78 Hz, 1H); 3.96 (s, 3H); 2.46 (br. s., 3H). 19F NMR (377 MHz, d6-DMSO) δ −139.31 (d, J=11.44 Hz, 1F).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:9][CH2:10][C@H:11]2[CH2:16][CH2:15][C@H:14]([CH:17]3[CH2:22][CH2:21][SiH:20](Cl)[CH2:19][CH2:18]3)[CH2:13][CH2:12]2)[CH:5]=[CH:6][C:7]=1[F:8].[CH2:24]1[CH2:28]OC[CH2:25]1>>[F:1][C:2]1[CH:3]=[C:4]([O:9][CH2:10][C@H:11]2[CH2:16][CH2:15][C@H:14]([C@H:17]3[CH2:22][CH2:21][Si@H:20]([CH2:25][CH2:24][CH3:28])[CH2:19][CH2:18]3)[CH2:13][CH2:12]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: C1CCOC1
Reactant: Fc1ccc(OC[C@H]2CC[C@H](C3CC[SiH](Cl)CC3)CC2)cc1F
Product: CCC[Si@H]1CC[C@H]([C@H]2CC[C@H](COc3ccc(F)c(F)c3)CC2)CC1

Procedure:
2.5 g (20 mmols) of n-propyl bromide was dropped in a mixture of 0.5 g of magnesium (21 mmols) and 50 ml of THF to obtain a Grignard reagent. Subsequently, the solution was dropped in 50 ml of a THF solution of 7.2 g (20 mmols) of 4-(trans-4-(3,4-difluorophenyloxymethyl)cyclohexyl)-1-chloro-1-silacyclohexane to obtain a crude product. This product was found to be a mixture of trans and cis isomers with respect to the silacyclohexane ring. The product was after-treated by a usual manner and isolated through column chromatography to obtain 6.7 g (yield: 91%) of the intended trans-trans isomer product. The results of measurement of phase transition temperatures and the IR analysis are shown below.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=3)[N:15]=[CH:14][CH:13]=2)[CH:3]=1.[CH2:23]([N:27]([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:28][CH2:29][NH2:30])[CH2:24][CH2:25][CH3:26]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:30][CH2:29][CH2:28][N:27]([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:31][CH2:32][CH2:33][CH3:34])=[O:8])=[C:4]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=3)[N:15]=[CH:14][CH:13]=2)[CH:3]=1
Reactant: O=C(O)c1ccc(Cl)cc1Nc1ccnc2cc(Cl)ccc12
Reactant: CCCCN(CCN)CCCC
Product: CCCCN(CCCC)CCNC(=O)c1ccc(Cl)cc1Nc1ccnc2cc(Cl)ccc12

Procedure:
4-Chloro-2-(7-chloro-4-quinolylamino)benzoic acid is converted to the acid chloride which is reacted with 2-(di-n-butylamino)ethylamine as in Example 1 to give the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3](=[O:18])[C@H:4]([O:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[C:9](=O)[NH:10][CH:11]=[N:12]2)[CH3:5].[O:20]1[CH:24]=[CH:23][N:22]=[C:21]1[CH2:25][N:26]1[C:34]2[C:29](=[CH:30][C:31]([NH2:35])=[CH:32][CH:33]=2)[CH:28]=[N:27]1>>[CH3:1][N:2]([CH3:19])[C:3](=[O:18])[C@H:4]([O:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[C:9]([NH:35][C:31]1[CH:30]=[C:29]3[C:34](=[CH:33][CH:32]=1)[N:26]([CH2:25][C:21]1[O:20][CH:24]=[CH:23][N:22]=1)[N:27]=[CH:28]3)=[N:10][CH:11]=[N:12]2)[CH3:5]
Reactant: Nc1ccc2c(cnn2Cc2ncco2)c1
Reactant: C[C@@H](Oc1cccc2nc[nH]c(=O)c12)C(=O)N(C)C
Product: C[C@@H](Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4ncco4)c3)c12)C(=O)N(C)C
Yield: 80 %

Procedure:
Using the same procedure as in Example 18, (2R)—N,N-dimethyl-2-[(4-oxo-3,4-dihydroquinazolin-5-yl)oxy]propanamide (212 mg, 0.81 mmol) and 1-(1,3-oxazol-2-ylmethyl)-1H-indazol-5-amine (1 equivalents) were reacted to give the title compound as a beige foam (295 mg, 80%); NMR spectrum (CDCl3) 1.73 (d, 3H), 3.06 (s, 3H), 3.14 (s, 3H), 5.43 (q, 1H), 5.71 (s, 2H), 6.81 (d, 1H), 7.09 (s, 1H), 7.48-7.53 (m, 2H), 7.58-7.62 (m, 2H), 7.88 (d, 1H), 8.07 (s, 1H), 8.41 (s, 1H), 8.61 (s, 1H), 10.92 (br s, 1H); Mass spectrum MH+ 458.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[F:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1>>[F:9][C:10]1[CH:16]=[CH:15][C:13]([NH:14][C:2]2[CH:3]=[C:4]([NH2:8])[N:5]=[CH:6][N:7]=2)=[CH:12][CH:11]=1
Reactant: Nc1ccc(F)cc1
Reactant: Nc1cc(Cl)ncn1
Product: Nc1cc(Nc2ccc(F)cc2)ncn1

Procedure:
The title compound is prepared analogously as described in Example 114A from 6-chloro-pyrimidin-4-ylamine and 4-fluoroaniline.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][OH:21])[C:13](=[O:22])[NH:12][C:11]=2[N:10]=[C:9]1[Cl:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH2:25][CH3:26].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][OH:21])[C:13](=[O:22])[N:12]([CH2:25][CH3:26])[C:11]=2[N:10]=[C:9]1[Cl:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCI
Reactant: O=c1[nH]c2nc(Cl)n(Cc3ccccc3)c2c(=O)n1CCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCn1c(=O)n(CCCO)c(=O)c2c1nc(Cl)n2Cc1ccccc1
Temperature: 40 °C
Reaction time: 4 h
Yield: 318 %

Procedure:
To a solution of 7-benzyl-8-chloro-1-(3-hydroxypropyl)-1H-purine-2,6(3H,7H)-dione (150 mg, 0.449 mmol) in DMF (5 mL) was added iodoethane (0.16 g, 0.13 mmol), followed by potassium carbonate (0.4 g, 2.90 mmol). The mixture was stirred at 40° C. for 4 h. The reaction was cooled and diluted with ethyl acetate. The organic phase was washed with water and brine; then it was dried over sodium sulfate, filtered and concentrated to give 7-benzyl-8-chloro-3-ethyl-1-(3-hydroxypropyl)-1H-purine-2,6(3H,7H)-dione (0.15 g, 92.3% yield) as yellow oil. LCMS retention time 1.296 min; LCMS MH+ 363.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH:18]([CH3:20])[CH3:19])=[C:7]([Cl:21])[C:6]=1[Cl:22])=O.[C:23]([N:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)(=[S:25])[NH2:24].N>>[Cl:22][C:6]1[C:7]([Cl:21])=[C:8]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH:18]([CH3:20])[CH3:19])[CH:9]=[CH:10][C:5]=1[C:3]1[N:24]=[C:23]([N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[S:25][CH:2]=1
Reactant: NC(=S)N1CCCCC1
Reactant: CC(C)c1ccccc1Sc1ccc(C(=O)CBr)c(Cl)c1Cl
Agent: N
Product: CC(C)c1ccccc1Sc1ccc(-c2csc(N3CCCCC3)n2)c(Cl)c1Cl

Procedure:
The title compound 42 was prepared according to the procedure of Example 11 from compound 41 (30 mg, 0.07 mmole) and 1-thiocarbamyl piperidine. Yield: 21 mg, 65.6%. 1H-NMR (CDCl3, 500 MHz) δ 1.19 (d, J=8.5 Hz, 6H), 1.65 (m, 6H), 3.44–3.52 (m, 5H), ), 6.48 (d, J=8.4 Hz, 1H), 7.01 (s, 1H), 7.21 (m, 1H), 7.44–7.51 (m, 3H), 7.61 (d, J=8.4 Hz, 1H). MS (DCI/NH3) m/z 463 (M+H)+.