Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:18][CH2:19][CH2:20][N:21]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][C:29]([NH:32][CH:33]=O)=[C:28]([O:35][CH3:36])[CH:27]=2)[CH:23]=[N:22]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.CS(C1[N:42]=[CH:43][C:44]2[CH:50]=[CH:49][N:48]=[C:47]([NH:51][CH:52]3[CH2:57][CH2:56][O:55][CH2:54][CH2:53]3)[C:45]=2[N:46]=1)(=O)=O>>[CH3:36][O:35][C:28]1[CH:27]=[C:26]([C:24]2[CH:23]=[N:22][N:21]([CH2:20][CH2:19][OH:18])[CH:25]=2)[CH:31]=[CH:30][C:29]=1[NH:32][C:33]1[N:42]=[CH:43][C:44]2[CH:50]=[CH:49][N:48]=[C:47]([NH:51][CH:52]3[CH2:53][CH2:54][O:55][CH2:56][CH2:57]3)[C:45]=2[N:46]=1
Reactant: CS(=O)(=O)c1ncc2ccnc(NC3CCOCC3)c2n1
Reactant: COc1cc(-c2cnn(CCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c2)ccc1NC=O
Product: COc1cc(-c2cnn(CCO)c2)ccc1Nc1ncc2ccnc(NC3CCOCC3)c2n1

Procedure:
The title compound was prepared according to Example 43 using N-(4-(1-(2-(tert-butyldiphenylsilyloxy)ethyl)-1H-pyrazol-4-yl)-2-methoxyphenyl)formamide (Preparation 67) and 2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-4-yl)pyrido[3,4-d]pyrimidin-8-amine (Preparation 45). The intermediate silyl ether was purified using silica gel column chromatography eluting with 0 to 55% EtOAc in cyclohexane and the title compound was purified using silica gel column chromatography eluting with 0 to 5% MeOH in EtOAc (6 mg, 85%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH3:9][OH:10].C[O-].[Na+]>>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([O:10][CH3:9])=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: CO
Agent: C[O-]
Agent: [Na+]
Product: COc1ccc(Br)cn1
Temperature: 25 °C
Yield: 100.8 %

Procedure:
2,5-Dibromopyridine (200 g) and 28% sodium methoxide methanol solution (1535 g) were heated under reflux for 30 minutes, followed by cooling to room temperature. The mixture was partitioned between water (1.6 L) and tert-butylmethyl ether (1.6 L). The resulting organic layer was washed with brine (1 L) for 3 times, and then dried over anhydrous magnesium sulfate overnight. The dried organic layer was evaporated at 65° C., to give 160 g (96%) of the title compound as a brown oil.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH:15]([NH2:17])[CH3:16])[CH:6]=[N:7][C:8]=1[O:9][CH2:10][C:11]([F:14])([F:13])[F:12].[CH3:18][O:19][C:20]([C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([CH3:31])[N:30]=1)[C:25](O)=[O:26])=[O:21]>>[Cl:2][C:3]1[CH:4]=[C:5]([CH:15]([NH:17][C:25]([C:24]2[CH:28]=[C:29]([CH3:31])[N:30]=[C:22]([C:20]([O:19][CH3:18])=[O:21])[CH:23]=2)=[O:26])[CH3:16])[CH:6]=[N:7][C:8]=1[O:9][CH2:10][C:11]([F:12])([F:13])[F:14]
Reactant: CC(N)c1cnc(OCC(F)(F)F)c(Cl)c1
Reactant: COC(=O)c1cc(C(=O)O)cc(C)n1
Agent: Cl
Product: COC(=O)c1cc(C(=O)NC(C)c2cnc(OCC(F)(F)F)c(Cl)c2)cc(C)n1

Procedure:
The title compound is prepared from (+)-1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (Amine-5, single enantiomer) and 2-(methoxycarbonyl)-6-methylisonicotinic acid by the similar manner in Step-1 of Example 8.
Reaction SMILES: [N:1]1([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:13][CH2:12][CH2:11][C@H:2]1[C:3]([NH:5][C@H:6]([C:8]([OH:10])=O)[CH3:7])=[O:4].ON1C2C=CC=CC=2N=N1.CN(CCCN=C=NCC)C.Cl.[NH2:46][C@H:47]([C:54]([O:56][CH3:57])=[O:55])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.Cl.CN1CCOCC1>C(Cl)Cl>[N:1]1([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:13][CH2:12][CH2:11][C@H:2]1[C:3]([NH:5][C@H:6]([C:8]([NH:46][C@H:47]([C:54]([O:56][CH3:57])=[O:55])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:10])[CH3:7])=[O:4]
Reactant: C[C@H](NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1)C(=O)O
Reactant: COC(=O)[C@@H](N)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A suspension of 1,500 g (4.68 mmoles) of Z-(L)-Pro-(L)-AlaOH (Sigma) in 60 ml of dry methylene chloride (CH2Cl2) was brought, under stirring and in an argon atmosphere, to the temperature of the ice and salt bath. The following were then added in succession: 0.800 g (4.73 mmoles) of commercial 1-hydroxybenzotriazole (HOBt) and 0.900 g (4.69 mmoles) of N-(dimethylaminopropyl)-N'-ethylcarbodiimide.HCl (EDC). Keeping the temperature under control, the mixture was left under stirring for 10 minutes and then the following were added in succession: 0.940 g (4.66 mmoles) of (L)-PhgOMe.HCl (Bachem) and 0.520 ml (4.72 mmoles) of 4-methylmorpholine (NMM), maintaining the temperature for a further 2 hours. The mixture was then left under stirring and static argon for 12 hours with the temperature free to rise to room temperature. The solid white precipitate was filtered away and washed with a little CH2Cl2. The latter was put back into the filtered reaction solution, which was extracted in succession using 5% NaHCO3 (3×30 ml); saturated aqueous NaCl (2×30 ml); 4% KHSO4 (3×30 ml) and finally saturated aqueous NaCl (2 ×30 ml), discarding the aqueous phases. The organic phase extracted was left in a cold chamber under argon and on anhydrous Na2SO4 for 12 hours. The desiccant was then filtered away, the solution concentrated to a small volume and the dense residual liquid was ground with anhydrous ethyl ether a number of times, decanting each time and discarding the ether phase. The residual solid was left for 24 hours under vacuum on P2O5. 1.630 g (74.8%) of an analytically pure powdery white solid were recovered.
Reaction SMILES: [C:1]([CH:4]([C:10]1[N:18]2[C:13]([C:14](=[O:30])[NH:15][C:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=3)=[N:17]2)=[C:12]([CH3:31])[N:11]=1)[CH2:5][CH2:6][CH2:7][CH:8]=[CH2:9])(=[O:3])[CH3:2].[BH4-].[Na+]>>[CH3:29][O:28][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][C:23]=1[O:26][CH3:27])[CH2:19][C:16]1[NH:15][C:14](=[O:30])[C:13]2=[C:12]([CH3:31])[N:11]=[C:10]([CH:4]([CH:1]([OH:3])[CH3:2])[CH2:5][CH2:6][CH2:7][CH:8]=[CH2:9])[N:18]2[N:17]=1
Reactant: C=CCCCC(C(C)=O)c1nc(C)c2c(=O)[nH]c(Cc3ccc(OC)c(OC)c3)nn12
Agent: [BH4-]
Agent: [Na+]
Product: C=CCCCC(c1nc(C)c2c(=O)[nH]c(Cc3ccc(OC)c(OC)c3)nn12)C(C)O

Procedure:
90 mg (0.20 mmol) of 7-(1-acetyl-5-hexenyl)-2-(3,4-dimethoxylbenzyl)-5-methylimidazo[5,1-f][1,2,4]triazin-4(3H)-one (Example 7) are reacted analogously to Example 8 with 8 mg (0.20 mmol) of sodium borohydride to give 2-(3,4-dimethoxybenzyl)-7-[1-(1-hydroxyethyl)-5-hexenyl]-5-methylimidazo[5,1-f][1,2,4]triazin-4(3H)-one.
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]([O:13][C:14]2[CH:19]=[C:18]([F:20])[C:17]([C:21]([F:24])([F:23])[F:22])=[C:16]([Cl:25])[CH:15]=2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])([O-])=O.[OH:26][C:27]1[CH:39]=[CH:38][C:30]([O:31][CH:32]([CH3:37])[C:33]([O:35][CH3:36])=[O:34])=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C.C(Cl)Cl>[Cl:25][C:16]1[CH:15]=[C:14]([O:13][C:6]2[CH:7]=[CH:8][C:9]([N+:10]([O-:12])=[O:11])=[C:4]([CH:5]=2)[O:26][C:27]2[CH:28]=[CH:29][C:30]([O:31][CH:32]([CH3:37])[C:33]([O:35][CH3:36])=[O:34])=[CH:38][CH:39]=2)[CH:19]=[C:18]([F:20])[C:17]=1[C:21]([F:22])([F:23])[F:24]
Reactant: COC(=O)C(C)Oc1ccc(O)cc1
Reactant: O=[N+]([O-])c1ccc(Oc2cc(F)c(C(F)(F)F)c(Cl)c2)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Solvent: O
Product: COC(=O)C(C)Oc1ccc(Oc2cc(Oc3cc(F)c(C(F)(F)F)c(Cl)c3)ccc2[N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 23.2 %

Procedure:
A mixture of 2-chloro-α,α,α,6-tetrafluoro-p-tolyl 3,4-dinitrophenyl ether (5.0 g, 0.013 mol), methyl 2-(p-hydroxyphenoxy)propionate (5.15 g, 0.026 mol) and potassium carbonate (3.6 g, 0.026 mol) in acetonitrile is refluxed for 18 hours, cooled to room temperature, poured into water and extracted with ether. The organic extract is washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to obtain a residue. Column chromatography of the residue using silica gel and methylene chloride gives an oil. A solution of the oil in ether is washed sequentially with saturated sodium hydrogen carbonate solution and water, dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the title product as a yellow oil (1.6 g) which is identified by 1HNMR and 13CNMR spectral analyses.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:11][C:12]1[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[C:13]=1[NH2:14].C([O:23][C:24]([C:26]1[CH:30]=[C:29]([C:31]2[CH:36]=[CH:35][N:34]=[C:33]([NH:37][C:38]3[CH:43]=[CH:42][C:41]([N:44]4[CH2:49][CH2:48][N:47]([CH3:50])[CH2:46][CH2:45]4)=[CH:40][C:39]=3[O:51][CH3:52])[N:32]=2)[N:28]([CH3:53])[CH:27]=1)=O)C>C1COCC1>[CH3:11][C:12]1[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[C:13]=1[NH:14][C:24]([C:26]1[CH:30]=[C:29]([C:31]2[CH:36]=[CH:35][N:34]=[C:33]([NH:37][C:38]3[CH:43]=[CH:42][C:41]([N:44]4[CH2:45][CH2:46][N:47]([CH3:50])[CH2:48][CH2:49]4)=[CH:40][C:39]=3[O:51][CH3:52])[N:32]=2)[N:28]([CH3:53])[CH:27]=1)=[O:23]
Reactant: CCOC(=O)c1cc(-c2ccnc(Nc3ccc(N4CCN(C)CC4)cc3OC)n2)n(C)c1
Reactant: Cc1cc(C)c(N)c(C)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(N2CCN(C)CC2)ccc1Nc1nccc(-c2cc(C(=O)Nc3c(C)cc(C)cc3C)cn2C)n1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 73.6 %

Procedure:
NaHMDS in THF (1.0 M, 11.0 mL, 11.0 mmol) was added over 30 min to a solution of 2,4,6-trimethylaniline (1.2 mL, 8.32 mmol) and 5-{2-[2-methoxy-4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-1H-pyrrole-3-carboxylic acid ethyl ester (1.25 g, 2.77 mmol) in THF (30 mL) at 0° C. The resulting brown solution was stirred at 0° C. for 10 min and allowed to warm to room temperature over a period of 20 min. After stirring at room temperature for 4 h, the reaction was quenched by the addiction of saturated aqueous NH4Cl (10 mL). The reaction was partitioned between ethyl acetate (50 mL) and water (50 mL). The aqueous layer was extracted with ethyl acetate (2×30 mL). The combined organic solution was washed with brine (50 mL), dried over Na2SO4, filtered and evaporated to dryness, the crude solid was purified by flash chromatography on silica gel (eluant: dichloromethane/methanol 95/5) to afford 1.10 g (72% yield) of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[F:12][C:13]1[CH:14]=[C:15]([CH:17]=[C:18]([F:20])[CH:19]=1)[NH2:16]>>[F:12][C:13]1[CH:14]=[C:15]([NH:16][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][C:9]([OH:11])=[O:10])[CH:17]=[C:18]([F:20])[CH:19]=1
Reactant: O=C(O)Cc1ccccc1Br
Reactant: Nc1cc(F)cc(F)c1
Product: O=C(O)Cc1ccccc1Nc1cc(F)cc(F)c1

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 3,5-difluoroaniline to yield 2-[(3,5-difluorophenyl)amino]phenylacetic acid.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18](=[O:20])[NH2:19])=[CH:12][C:10]=3[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21]([OH:24])(=[O:23])[CH3:22]>>[C:21]([O:24][CH:11]([C:10]1[CH:9]=[CH:15][CH:14]=[C:13]([O:16][CH2:17][C:18](=[O:20])[NH2:19])[CH:12]=1)[C:7](=[O:8])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)O
Reactant: NC(=O)COc1ccc2oc(-c3ccccc3)cc2c1
Product: CC(=O)OC(C(=O)c1ccccc1)c1cccc(OCC(N)=O)c1

Procedure:
Irradiation of 7 resulted in a clean conversion to the phenylbenzofurans 8 and 9. Steady-state photolysis spectra of 7 show two isosbestic points throughout the course of the photolysis (FIG. 3). The two isomeric photoproducts 8 and 9 were produced in a 98% yield at a ratio of 3:1 as determined by GCMS and NMR of the isolated phenylbenzofurans, along with an equivalent of acetic acid.
Reaction SMILES: [NH2:1][C@H:2]([C:15]([NH:17][C@H:18]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[CH2:19][CH:20]([CH3:22])[CH3:21])=[O:16])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:6][CH:5]=1.C1C=CC2N(O)N=NC=2C=1.[NH:43](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H:44]([C:54](O)=[O:55])[CH2:45][CH2:46][C:47](=[O:53])[O:48][C:49]([CH3:52])([CH3:51])[CH3:50].CCN=C=NCCCN(C)C.Cl.C(O)(=O)C(CC(O)=O)S.C1CCN2C(=NCCC2)CC1.S(O)(C)(=O)=O>[Cl-].[Na+].O.C(Cl)(Cl)Cl>[NH2:43][C@H:44]([C:54]([NH:1][C@H:2]([C:15]([NH:17][C@H:18]([C:23]([O:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[O:24])[CH2:19][CH:20]([CH3:22])[CH3:21])=[O:16])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]([CH3:13])([CH3:14])[CH3:12])=[CH:8][CH:9]=1)=[O:55])[CH2:45][CH2:46][C:47](=[O:53])[O:48][C:49]([CH3:51])([CH3:52])[CH3:50]
Reactant: CC(C)C[C@H](NC(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1)C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClC(Cl)Cl
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)[C@@H](N)CCC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the chloroform solution (20 ml) of H-Tyr(tBu)-Leu-OBzl was added HOBt (41 mg, 0.30 mmol), Fmoc-Glu(OtBu)-OH (468 mg, 1.10 mmol) and EDC.HCl (232 mg, 1.21 mmol) were added under ice-cooling, and the mixture was stirred at room temperature overnight. After completion of the reaction, to this solution were added under ice-cooling thiomalic acid (450 mg, 3.00 mmol) and DBU (1.49 mL, 10.00 mmol), and the mixture was stirred at room temperature for 3 hr. After completion of the reaction, to this solution was added dropwise under ice-cooling a mixture of MsOH (0.23 mL, 3.60 mmol) and chloroform (2.3 mL), chloroform (10 ml) and 20% brine (20 ml) were added to give an organic layer and an aqueous layer. Then, the aforementioned pH=9.0 washing was performed three times. The obtained organic layer was washed three times with 10% aqueous sodium carbonate solution (20 ml) and twice with 20% brine (20 ml) with stirring at room temperature, and the organic layer and the aqueous layer were partitioned. The obtained organic layer was dried over sodium sulfate and filtered to give a chloroform solution (30 ml) of H-Glu(OtBu)-Tyr(tBu)-Leu-OBzl. This chloroform solution was directly used in the next step.
Reaction SMILES: [F:1][C:2]([Si](C)(C)C)([F:4])[F:3].[CH3:9][C:10]1[N:11]=[CH:12][S:13][C:14]=1[C:15]([C:17]1[S:21][CH:20]=[N:19][C:18]=1[CH3:22])=[O:16].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl.CC1C=CC(COC(NNC(C2C=NC=CN=2)=O)=O)=CC=1.[OH-].[K+]>O1CCCC1>[CH3:22][C:18]1[N:19]=[CH:20][S:21][C:17]=1[C:15]([C:14]1[S:13][CH:12]=[N:11][C:10]=1[CH3:9])([OH:16])[C:2]([F:4])([F:3])[F:1]
Reactant: Cc1ncsc1C(=O)c1scnc1C
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cc1ccc(COC(=O)NNC(=O)c2cnccn2)cc1
Agent: Cl
Solvent: C1CCOC1
Product: Cc1ncsc1C(O)(c1scnc1C)C(F)(F)F
Reaction time: 1 h

Procedure:
(Trifluoromethyl)trimethylsilane (494 μl) was added to a stirred solution of bis(4-methyl-5-thiazolyl) ketone (500 mg) in anhydrous tetrahydrofuran (20 ml) at room temperature. After 1 hour, tetrabutylammonium fluoride (300 mg) was added. The mixture was stirred for 2 hours and then 3M hydrochloric acid was added. After 10 minutes the reaction mixture was adjusted to pH10 by the addition of 5M potassium hydroxide. The organic phase was separated and then worked-up in the usual manner to give the title compound.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15](=[O:21])[NH:16][CH:17]=[N:18]2)=[CH:13][C:12]=1[O:22][CH3:23])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:24]([O:30][CH2:31]Cl)(=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26].Cl>CN(C=O)C.C(OCC)(=O)C>[CH2:3]([O:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15](=[O:21])[N:16]([CH2:31][O:30][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[CH:17]=[N:18]2)=[CH:13][C:12]=1[O:22][CH3:23])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCc1ccccc1
Reactant: CC(C)(C)C(=O)OCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCc1ccccc1
Reaction time: 1.5 h
Yield: 84.1 %

Procedure:
Sodium hydride (1.44 g of a 60% suspension in mineral oil, 36 mmol) was added in portions over 20 minutes to a solution of 7-benzyloxy-6-methoxy-3,4-dihydroquinazolin-4-one (8.46 g, 30 mmol), (prepared as described for the starting material in Example 1), in DMF (70 ml) and the mixture was stirred for 1.5 hours. Chloromethyl pivalate (5.65 g, 37.5 mmol) was added dropwise and the mixture stirred for 2 hours at ambient temperature. The mixture was diluted with ethyl acetate (100 ml) and poured onto ice/water (400 ml) and 2M hydrochloric acid (4 ml). The organic layer was separated and the aqueous layer extracted with ethyl acetate, the combined extracts were washed with brine, dried (MgSO4) and the solvent removed by evaporation. The residue was triturated with a mixture of ether and petroleum ether, the solid was collected by filtration and dried under vacuum to give 7-benzyloxy-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (10 g, 84%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.C[N:13](C)[CH:14]=[O:15].C[Si](N=C=O)(C)C>O1CCCC1>[NH:1]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2)[C:14]([NH2:13])=[O:15]
Reactant: Nc1ccc2c(c1)CC(=O)N2
Reactant: CN(C)C=O
Agent: C[Si](C)(C)N=C=O
Solvent: C1CCOC1
Product: NC(=O)Nc1ccc2c(c1)CC(=O)N2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 5-aminoindolin-2-one (8.76, 58.79 mmol) in tetrahydrofuran:dimethylformamide (400 mL:60 mL) was added trimethylsilylisocyanate (10.6 mL, 78.68 mmol) dropwise. The reaction mixture was stirred at ambient temperature for 18 hours. A tan-colored solid formed which was isolated by filtration, washed with ether and dried in vacuo to afford 5-ureidoindolin-2-one (8.5 g).
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH:5]=[CH2:6].[CH3:7][SiH2:8][O:9][Si:10]([CH3:13])([CH3:12])[CH3:11]>[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl>[CH2:1]([Si:8]([CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=[CH2:1])([CH3:7])[O:9][Si:10]([CH3:13])([CH3:12])[CH3:11])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6]
Reactant: C[SiH2]O[Si](C)(C)C
Reactant: C=CCCC=C
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Product: C=CCCCC[Si](C)(CCCCC=C)O[Si](C)(C)C
Temperature: 80 °C
Yield: 59.6 %

Procedure:
After 410 g (5 mol) of 1,5-hexadiene and 0.035 g of chloroplatinic acid had been placed into a 1 L three-necked flask equipped with an agitation mechanism, the contents were agitated. Then, 134 g (1 mol) of tetramethyldisiloxane were added dropwise into the resulting mixture for approximately 1.5 h while the temperature was being gradually raised to 80° C. Then, the contents were reacted at 80° C. for an additional 2 h. After unreacted components had been distilled and removed from the resulting mixture at 80° C. and 3 mm Hg, 178 g of di(5-hexenyl)tetramethyldisiloxane were obtained. 1H-NMR and 13C-NMR analyses revealed that the objective product had been synthesized.
Reaction SMILES: [NH2:1][C:2](=[O:44])[CH2:3][C:4]1[CH:43]=[CH:42][CH:41]=[CH:40][C:5]=1[CH2:6][CH2:7][C:8]1[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][N:11]=[C:10]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH:25]3[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]3)=[CH:21][C:20]=2[O:38][CH3:39])[N:9]=1.C(O)(C(F)(F)F)=O>ClCCl>[CH3:39][O:38][C:20]1[CH:21]=[C:22]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:23]=[CH:24][C:19]=1[NH:18][C:10]1[N:9]=[C:8]([CH2:7][CH2:6][C:5]2[CH:40]=[CH:41][CH:42]=[CH:43][C:4]=2[CH2:3][C:2]([NH2:1])=[O:44])[C:13]([C:14]([F:15])([F:16])[F:17])=[CH:12][N:11]=1
Reactant: COc1cc(C2CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1ncc(C(F)(F)F)c(CCc2ccccc2CC(N)=O)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C2CCNCC2)ccc1Nc1ncc(C(F)(F)F)c(CCc2ccccc2CC(N)=O)n1
Reaction time: 16 h
Yield: 99.9 %

Procedure:
A solution of tert-butyl 4-(4-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidine-1-carboxylate (I23) (2.694 g, 4.39 mmol) was dissolved in dichloromethane (150 mL), and TFA (15 mL) was added. The resulting mixture was stirred for 16 hours then concentrated. The residue was suspended in 10% sodium hydroxide (200 mL) then extracted with ethyl acetate (5×200 mL). The combined organic phases were washed with brine (300 mL), dried over sodium sulfate and evaporated to give the title compound (2) (2.252 g, 100% yield) as a white solid; 1H NMR (400 MHz, CDCl3) δ 8.53 (s, 1H), 8.26 (d, J=8.3 Hz, 1H), 7.85 (s, 1H), 7.29-7.21 (m, overlaps with CHCl3), 6.87 (d, J=8.3 Hz, 1H), 6.80 (s, 1H), 5.43 (d, J=10.1 Hz, 2H), 3.92 (d, J=1.3 Hz, 3H), 3.70 (s, 2H), 3.20 (d, J=12.7 Hz, 2H), 3.15-3.05 (m, 4H), 2.75 (t, J=12.2 Hz, 2H), 2.61 (tt, J=12.0, 3.5 Hz, 1H), 1.89-1.76 (m, overlaps with water), 1.67 (qd, J=12.7, 3.9 Hz, 2H). LCMS Method C: rt 4.92 min; m/z 514.1 [M+H]+, 536.1 [M+Na]+; m/z 512.2 [M−H]−.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7](O)=[O:8])[C:5]([NH2:11])=[CH:4][CH:3]=1.CSC.B.[OH-].[Na+].C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[NH2:11][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:10][C:6]=1[CH2:7][OH:8]
Reactant: Nc1ccc(Br)cc1C(=O)O
Agent: B
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CSC
Product: Nc1ccc(Br)cc1CO
Temperature: 0 °C
Reaction time: 4.5 h
Yield: 97.8 %

Procedure:
In THF (350 ml) was dissolved 5-bromoanthranilic acid (40.06 g), and the mixture was cooled to 0° C. To the mixture was added dropwise a solution of 10.0M borane dimethyl-sulfide in THF (54.5 ml), and the mixture was stirred at room temperature for 4.5 hours. The mixture was cooled to 0° C., and to the mixture was added dropwise 3N sodium hydroxide solution. The mixture was stirred at room temperature overnight, and to the mixture was added granulated sodium hydroxide to adjust the mixture to pH 11. The aqueous layer was saturated with potassium carbonate, and the THF layer was separated. The aqueous layer was extracted with ether (100 ml×5). The organic layers were combined and dried with magnesium sulfate. The solvent was evaporated under reduced pressure to give (2-amino-5-bromophenyl)methanol (36.66 g, 100%).
Reaction SMILES: [CH:1]1([N:7]([CH2:25][CH:26]2[CH2:28][CH2:27]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH:23]=O)=[CH:19][CH:18]=3)=[O:15])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[C:30]([O:34][C:35](=[O:38])[CH2:36][NH2:37])([CH3:33])([CH3:32])[CH3:31].C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(Cl)Cl>[CH:1]1([N:7]([CH2:25][CH:26]2[CH2:27][CH2:28]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([CH2:23][NH:37][CH2:36][C:35]([O:34][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:38])=[CH:21][CH:22]=3)=[O:15])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1ccc(NC(=O)c2cc(N(CC3CC3)C3CCCCC3)ncn2)cc1
Reactant: CC(C)(C)OC(=O)CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CNCc1ccc(NC(=O)c2cc(N(CC3CC3)C3CCCCC3)ncn2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 70.6 %

Procedure:
A solution of 6-[cyclohexyl(cyclopropylmethyl)amino]-N-(4-formylphenyl)pyrimidine-4-carboxamide (Intermediate 24, 80 mg; 0.18 mmol) in DCM (8 ml) was treated with Glycine tert-butyl ester hydrochloride (Sachem, 60.6 mg; 0.36 mmol) and triethylamine (50 μl; 0.36 mmol). After 2 minutes sodium triacetoxyborohydride (96 mg; 0.45 mmol) and acetic acid (2 μl; 0.04 mmol) were added and the reaction was stirred at room temperature for 20 hours. The solvent was removed under vacuum and the residue was redissolved in EtOAc. The organic phase was washed twice with an aqueous solution (1N) of NaOH and once with brine, dried (MgSO4) and the solvent removed under vacuum to afford the title compound as a colorless oil (62.7 mg, 70%) after purification by column chromatography (silica) eluting with cyclohexane containing increasing amounts of EtOAc.