Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:22]=[CH:21][C:7]([O:8][CH2:9][CH2:10][O:11][CH2:12][C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=2)[C:16]#[N:17])=[CH:6][CH:5]=1.C(N(C(C)C)CC)(C)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>ClCCl>[CH3:32][S:33]([O:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][CH2:10][O:11][CH2:12][C:13]2[CH:20]=[CH:19][CH:18]=[C:15]([C:16]#[N:17])[CH:14]=2)=[CH:21][CH:22]=1)(=[O:35])=[O:34]
Reactant: N#Cc1cccc(COCCOc2ccc(CCO)cc2)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)OCCc1ccc(OCCOCc2cccc(C#N)c2)cc1
Reaction time: 2 h

Procedure:
To a solution of 3-({2-[4-(2-hydroxyethyl)phenoxy]ethoxy}methyl)benzonitrile (5.04 g) and diisopropylethylamine (5.94 ml) in dichloromethane (50 ml) at 0° C. was added methanesulphonyl chloride (1.58 ml) dropwise and the mixture allowed to stir for 2 h. The resultant mixture was partitioned between dichloromethane and saturated sodium hydrogen carbonate. The organic phase was dried (MgSO4) and concentrated in vacuo to give the title compound (6.02 g). LCMS RT=3.22 min.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23](=[O:25])[CH3:24])=[CH:19][CH:18]=3)=[O:16])[CH2:6][C:5]=12.C(O[CH:31](N(C)C)[N:32]([CH3:34])[CH3:33])(C)(C)C>ClCCl>[CH3:31][N:32]([CH3:34])[CH:33]=[CH:24][C:23]([C:20]1[CH:19]=[CH:18][C:17]([C:15]([N:7]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][N:4]3[CH:3]=[CH:2][CH:1]=[C:5]3[CH2:6]2)=[O:16])=[CH:22][CH:21]=1)=[O:25]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: CC(=O)c1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Solvent: ClCCl
Product: CN(C)C=CC(=O)c1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Reaction time: 18 h

Procedure:
A reaction mixture of 1-[4-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepine-10-carbonyl)-phenyl]-ethanone (1.40 g), t-butoxy-bis-dimethylaminomethane (5.0 ml) and dichloromethane (10 ml) was stirred for 18 hours. The red-orange precipitate was filtered to yield the title compound (1.22 g), m.p. 203-205° C. Additional product (0.18 g) was isolated from the reaction mixture by concentration.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C@@H:8]([NH:10][C:11]2[N:16]=[C:15]([N:17]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[N:19]=[CH:18]3)[CH:14]=[CH:13][N:12]=2)[CH3:9])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:33](Cl)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(Cl)Cl>[C:33]([NH:1][C:2]1[CH:3]=[C:4]([C@@H:8]([NH:10][C:11]2[N:16]=[C:15]([N:17]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[N:19]=[CH:18]3)[CH:14]=[CH:13][N:12]=2)[CH3:9])[CH:5]=[CH:6][CH:7]=1)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: C[C@H](Nc1nccc(-n2cnc3ccccc32)n1)c1cccc(N)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](Nc1nccc(-n2cnc3ccccc32)n1)c1cccc(NC(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-[(S)-1-(3-aminophenyl)ethylamino]-4-[benzimidazol-1-yl]pyrimidine (10.0 mg) in CH2Cl2 (2 mL) was added triethylamine (13 μL) and benzoyl chloride (3.5 μL). The resulting solution was stirred at room temperature for 30 min. then the volatiles removed in vacuo. The residue was purified on silica gel (2%(2M NH3 in MeOH)/CH2Cl2) then HPLC (Zorbax Rx-SIL, 70:30 hexanes:ethanol) to yield 1.8 mg of the title compound. 1H NMR (500 MHz, CDCl3, partial): δ 8.41 (d, J=5.5 Hz, 1H); 7.87 (m, 2H); 7.82 (m, 2H); 7.76 (s, 1H); 7.58 (m, 2H); 7.51 (m, 2H); 7.41 (t, J=7.9 Hz, 1H); 6.80 (d, J=5.5 Hz, 1H); 1.67 (d, J=6.9 Hz, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[N:10][C:9]([NH:12]O)=[CH:8][N:7]=1)[CH3:2]>CO.[OH-].[OH-].[Pd+2]>[NH2:12][C:9]1[N:10]=[CH:11][C:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:14])=[N:7][CH:8]=1
Reactant: CCOC(=O)Cc1cnc(NO)cn1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCOC(=O)Cc1cnc(N)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of ethyl[5-(hydroxyamino)pyrazin-2-yl]acetate (2.8 g, 14.2 mmol) and Pd(OH)2 (3 g, 10%) in 150 mL of methanol was stirred at room temperature under 50 psi of H2 for 2 hours before filtration. The filtrate was concentrated to afford ethyl (5-aminopyrazin-2-yl)acetate.
Reaction SMILES: [CH2:1]([N:8]1[C:14](=O)[C:13]2[CH:16]=[CH:17][N:18]=[C:19]([Cl:20])[C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO>C1COCC1>[CH2:1]([N:8]1[CH2:14][C:13]2[CH:16]=[CH:17][N:18]=[C:19]([Cl:20])[C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2ccnc(Cl)c2OCCN1Cc1ccccc1
Solvent: CO
Solvent: C1CCOC1
Product: Clc1nccc2c1OCCN(Cc1ccccc1)C2
Temperature: 90 °C
Reaction time: 1 h
Yield: 78.8 %

Procedure:
To a solution of the compound (2.40 g) obtained in step 5 in THF (30 mL) was added 1M BH3.THF complex/THF solution (41.5 mL) was added at 0° C., and the mixture was stirred at 90° C. for 1 hr. After the reaction mixture was cooled to 10° C., MeOH (10 mL) was added, and the mixture was concentrated under reduced pressure. The residue was suspended in MeOH (15 mL) and 6N hydrochloric acid (15 mL), and the mixture was stirred at 80° C. for 1 hr. The reaction mixture was cooled to 10° C., and made basic with aqueous sodium hydroxide solution, and the resultant product was extracted with ethyl acetate. The organic layer was washed with brine, and concentrated. The residue was purified by silica gel column chromatography (solvent; 5% ethyl acetate/hexane) to give the title compound (1.80 g, 79%) as a colorless oil.
Reaction SMILES: [N+:1](=[C:3]1[C:8](=[O:9])[CH2:7][CH2:6][CH2:5][C:4]1=[O:10])=[N-].[F:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][C:18]=1[F:19])N>>[F:11][C:12]1[CH:13]=[C:14]([N:1]([C:3]2[C:8](=[O:9])[CH2:7][CH2:6][CH2:5][C:4]=2[OH:10])[C:3]2[C:8](=[O:9])[CH2:7][CH2:6][CH2:5][C:4]=2[OH:10])[CH:16]=[CH:17][C:18]=1[F:19]
Reactant: Nc1ccc(F)c(F)c1
Reactant: [N-]=[N+]=C1C(=O)CCCC1=O
Product: O=C1CCCC(O)=C1N(C1=C(O)CCCC1=O)c1ccc(F)c(F)c1

Procedure:
Following the procedure described in the Example 1, using 2-diazo-cyclohexane-1,3-dione and 3,4-difluoroaniline as starting materials to yield the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][OH:8])=[NH:6].[Cl:12][CH2:13][C:14](O)=O.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>CN(C)C=O.C(OCC)(=O)C>[Cl:12][CH2:13][C:14]1[O:8][N:7]=[C:5]([C:4]2[CH:9]=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=2)[N:6]=1
Reactant: N=C(NO)c1cccc(F)c1
Reactant: O=C(O)CCl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Fc1cccc(-c2noc(CCl)n2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.6 %

Procedure:
3-Fluoro-N-hydroxy-benzamidine (1.4 g, 9.08 mmol), chloroacetic acid (0.94 g, 9.99 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.91 g, 9.99 mmol) and 1-hydroxybenzotriazole hydrate (1.35 g, 9.99 mmol) were mixed in N,N-dimethylformamide (15 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (50 mL), washed with water (50 mL), washed with aqueous saturated sodium bicarbonate (75 mL), washed with water again (50 mL) and washed with brine (50 mL). The organic phase was dried over sodium sulfate and concentrated to give a solid. The solid was dissolved in N,N-dimethylformamide (10 mL) and the reaction mixture stirred at 120° C. for 1.5 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (100 mL), washed with water (3×50 mL) and washed with brine (50 mL). The organic phase was dried over sodium sulfate and concentrated. The residue was purified on silica gel eluting with 10 to 30% ethyl acetate in hexanes to give the product as a yellow oil (1.15 g, 60%). 1H NMR (300 MHz, CDCl3): δ 7.91 (dd, 1H), 7.82 (m, 1H), 7.5 (m, 1H), 7.25 (m, 1H), 4.78 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N+](=[CH2:16])=[N-]>CO>[CH3:16][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:2]=1[NH2:1]
Reactant: Nc1c(C(=O)O)cccc1[N+](=O)[O-]
Reactant: C=[N+]=[N-]
Solvent: CO
Product: COC(=O)c1cccc([N+](=O)[O-])c1N

Procedure:
To a solution of 2-amino-3-nitro-benzoic acid (6 g, 33 mmol) in methanol (20 mL), an ethereal solution of diazomethane gas was added until the staring material is completely consumed. The reaction mixture was then evaporated under reduced pressure and the crude resulting solid was purified by flash column chromatography using 5% ethylacetate & hexane as an eluent, to obtain 2 g of the required product as a yellow coloured solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.[NH:9]1[CH2:14][CH2:13][S:12](=[O:16])(=[O:15])[CH2:11][CH2:10]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][C:5]([N:9]2[CH2:14][CH2:13][S:12](=[O:16])(=[O:15])[CH2:11][CH2:10]2)=[N:6][CH:7]=1
Reactant: O=S1(=O)CCNCC1
Reactant: Clc1ncc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=S1(=O)CCN(c2ncc(Br)cn2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.6 %

Procedure:
5-Bromo-2-chloropyrimidine (400 mg) was dissolved in DMF (4 ml), and thiomorpholine 1,1-dioxide (308 mg) and K2CO3 (857 mg) were added thereto, followed by stirring at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and then a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with CHCl3. The organic layer was dried over Na2SO4 and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3/MeOH) to obtain 4-(5-bromopyrimidin-2-yl)thiomorpholine 1,1-dioxide (191 mg).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([NH:13][C@H:14]1[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][CH2:15]1)=[N:8]2.[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1.C(O)(=O)C>ClC(Cl)C>[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH:1][CH2:2][C:3]2[CH:12]=[CH:11][CH:10]=[C:9]3[C:4]=2[CH:5]=[CH:6][C:7]([NH:13][C@H:14]2[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH2:16][CH2:15]2)=[N:8]3)=[CH:26][CH:25]=1
Reactant: NCc1cccc2nc(N[C@@H]3CCc4ccccc43)ccc12
Reactant: O=Cc1ccc(F)cc1
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: Fc1ccc(CNCc2cccc3nc(N[C@@H]4CCc5ccccc54)ccc23)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 47.4 %

Procedure:
A solution of (5-aminomethyl-quinolin-2-yl)-(R)-indan-1-yl-amine (example 80, step B) (200 mg, 0.69 mmol), 4-fluorobenzaldehyde (94 mg, 0.76 mmol) and acetic acid (166 mg, 2.76 mmol) in 1,1-dichloroethane (10 ml) was stirred at room temperature for 30 minutes. Afterwards sodium triacetoxy-boron hydride (342 mg, 1.61 mmol) was added, the reaction mixture was allowed to stir for 17 hours at room temperature, poured into ice/saturated NaHCO3 solution (20 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. The crude product was purified by flash chromatography (ethyl acetate/heptane) on silica gel to yield the title compound as light yellow oil (130 mg, 47%).
Reaction SMILES: C([O:8][C:9]1[CH:115]=[CH:114][C:12]([CH2:13][C@@H:14]([C:28]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([CH:37]([C:76]3[CH:81]=[CH:80][C:79]([NH:82][C:83](=[O:113])[C@H:84]([CH2:98][C:99]4[CH:104]=[CH:103][C:102]([O:105]CC5C=CC=CC=5)=[CH:101][CH:100]=4)[NH:85][C:86](=[O:97])[CH2:87][C:88]4[C:96]5[C:91](=[CH:92][CH:93]=[CH:94][CH:95]=5)[NH:90][CH:89]=4)=[CH:78][CH:77]=3)[C:38]3[CH:43]=[CH:42][C:41]([NH:44][C:45](=[O:75])[C@H:46]([CH2:60][C:61]4[CH:66]=[CH:65][C:64]([O:67]CC5C=CC=CC=5)=[CH:63][CH:62]=4)[NH:47][C:48](=[O:59])[CH2:49][C:50]4[C:58]5[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=5)[NH:52][CH:51]=4)=[CH:40][CH:39]=3)=[CH:33][CH:32]=2)=[O:29])[NH:15][C:16](=[O:27])[CH2:17][C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][CH:19]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1>CO.CN(C)C=O.[C].[Pd]>[NH:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:18]([CH2:17][C:16]([NH:15][C@H:14]([C:28]([NH:30][C:31]2[CH:32]=[CH:33][C:34]([CH:37]([C:38]3[CH:43]=[CH:42][C:41]([NH:44][C:45](=[O:75])[C@H:46]([CH2:60][C:61]4[CH:62]=[CH:63][C:64]([OH:67])=[CH:65][CH:66]=4)[NH:47][C:48](=[O:59])[CH2:49][C:50]4[C:58]5[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=5)[NH:52][CH:51]=4)=[CH:40][CH:39]=3)[C:76]3[CH:77]=[CH:78][C:79]([NH:82][C:83](=[O:113])[C@H:84]([CH2:98][C:99]4[CH:104]=[CH:103][C:102]([OH:105])=[CH:101][CH:100]=4)[NH:85][C:86](=[O:97])[CH2:87][C:88]4[C:96]5[C:91](=[CH:92][CH:93]=[CH:94][CH:95]=5)[NH:90][CH:89]=4)=[CH:80][CH:81]=3)=[CH:35][CH:36]=2)=[O:29])[CH2:13][C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:115][CH:114]=2)=[O:27])=[CH:19]1
Reactant: O=C(Cc1c[nH]c2ccccc12)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)Nc1ccc(C(c2ccc(NC(=O)[C@H](Cc3ccc(OCc4ccccc4)cc3)NC(=O)Cc3c[nH]c4ccccc34)cc2)c2ccc(NC(=O)[C@H](Cc3ccc(OCc4ccccc4)cc3)NC(=O)Cc3c[nH]c4ccccc34)cc2)cc1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(Cc1c[nH]c2ccccc12)N[C@@H](Cc1ccc(O)cc1)C(=O)Nc1ccc(C(c2ccc(NC(=O)[C@H](Cc3ccc(O)cc3)NC(=O)Cc3c[nH]c4ccccc34)cc2)c2ccc(NC(=O)[C@H](Cc3ccc(O)cc3)NC(=O)Cc3c[nH]c4ccccc34)cc2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 4.2 %

Procedure:
The tris[4-[O-benzyl-N-[2-(1H-indol-3-yl)acetyl]-L-tyrosyl]aminophenyl]methane (70 mg) obtained in Example 92 was dissolved in a mixed solvent of methanol (4 ml) and N,N-dimethylformamide (4 ml), 10% palladium carbon (25 mg) was added, and then the mixture was stirred for 3 days at room temperature under a hydrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. A portion of the residue was purified by preparative high performance liquid chromatography using methanol/trifluoroacetic acid (100/0.1) and water/trifluoroacetic acid (100/0.1) as a mixed eluent, to obtain 2.4 mg of the title compound.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Br:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH:18]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)[OH:19].CCN(CC)CC>C(Cl)Cl>[Br:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([C:20]1[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=1)=[O:19]
Reactant: OC(c1ccc(Cl)cc1)c1ccccc1Br
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc(Cl)cc1)c1ccccc1Br
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-bromobenzaldehyde (3.15 ml, 27.0 mmol) and THF (135 ml) at 0° C. was added (4-chlorophenyl)magnesium bromide solution (29.7 ml, 1M in THF, 29.7 mmol). The reaction was stirred at 0° C. for 30 min before addition of a saturated solution of ammonium chloride. The layers were separated and the aqueous extracted with EtOAc. The combined organics were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude residue was purified via Biotage to afford (2-bromophenyl)(4-chlorophenyl)methanol. To a solution of DCM (100 ml) and oxalyl chloride (2.471 ml, 28.2 mmol) at −78° C. was added DMSO (3.34 ml, 47.0 mmol) and the reaction stirred at −78° C. for 15 min. After 15 min a solution of (2-bromophenyl)(4-chlorophenyl)methanol in DCM (25 ml) was added dropwise and stirred for 15 min at −78° C. before addition of Et3N (9.84 ml, 70.6 mmol). The cold bath was removed and the reaction was warmed to room temperature. To this solution was added water and the layers separated. The aqueous was extracted with DCM and the combined organics were dried over Na2SO4, filtered, and concentrated. The crude residue was purified via Biotage (EtOAc/hex) to afford (2-bromophenyl)(4-chlorophenyl)methanone. m/z (ESI) 295, 297 [M+H]+.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].C1(C)C=CC=CC=1.[NH2:12][C@H:13]([C:17]([O:19][CH3:20])=[O:18])[CH:14]([CH3:16])[CH3:15].Cl>>[CH3:20][O:19][C:17](=[O:18])[C@@H:13]([N:12]=[C:1]=[O:2])[CH:14]([CH3:16])[CH3:15]
Reactant: O=C(Cl)Cl
Reactant: COC(=O)[C@@H](N)C(C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H](N=C=O)C(C)C
Temperature: 25 °C

Procedure:
A solution of 1.9M phosgene in toluene (9.41 mL, 17.89 mmol) was added to a suspension of H-Val-OCH3.HCl (1.0 g, 5.96 mmol). The reaction mixture was heated at reflux for 2 h under a dry ice condenser, cooled to room temperature, sparged vigorously with nitrogen for 1.5 h and then concentrated to dryness. Toluene (5 mL) was added to the residue and the resulting solution concentrated to dryness to give (S)-2-isocyanato-3-methylbutanoic acid methyl ester. This product was dried under high vacuum for 5 min and then used in the following step. 1H NMR(CDCl3) δ3.95-3.94 (d, J=3.82 Hz, 1H), 3.81 (s, 3H), 2.35-2.22 (m, 1H), 1.04-1.02 (d, J=6.8 Hz, 3H), 0.91-0.89 (d, J=6.74 Hz, 3H).
Reaction SMILES: [CH:1]1([CH2:8][CH2:9][NH:10][C:11](=[O:42])[C@H:12]([CH3:41])[C@H:13]([C@@H:16]2[CH2:20][CH2:19][CH2:18][N:17]2[C:21](=[O:40])[CH2:22][C@@H:23]([O:38][CH3:39])[C@@H:24]([N:29]([CH3:37])[C:30](=[O:36])[C@H:31]([CH:33]([CH3:35])[CH3:34])[NH2:32])[C@@H:25]([CH3:28])[CH2:26][CH3:27])[O:14][CH3:15])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=[CH:2]1.[C:43]([O:47][C:48]([N:50]1[CH2:57][CH2:56][CH2:55][C@@:51]1([CH3:58])[C:52](O)=[O:53])=[O:49])([CH3:46])([CH3:45])[CH3:44].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>ClCCl>[C:43]([O:47][C:48]([N:50]1[CH2:57][CH2:56][CH2:55][C@@:51]1([CH3:58])[C:52]([NH:32][C@H:31]([C:30]([N:29]([C@@H:24]([C@@H:25]([CH3:28])[CH2:26][CH3:27])[C@H:23]([O:38][CH3:39])[CH2:22][C:21]([N:17]1[CH2:18][CH2:19][CH2:20][C@H:16]1[C@H:13]([O:14][CH3:15])[C@@H:12]([CH3:41])[C:11]([NH:10][CH2:9][CH2:8][CH:1]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=[CH:2]1)=[O:42])=[O:40])[CH3:37])=[O:36])[CH:33]([CH3:34])[CH3:35])=[O:53])=[O:49])([CH3:46])([CH3:44])[CH3:45]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@]1(C)C(=O)O
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)NCCC1C=CC=CC=C1)OC)N(C)C(=O)[C@@H](N)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)NCCC1C=CC=CC=C1)OC)N(C)C(=O)[C@@H](NC(=O)[C@]1(C)CCCN1C(=O)OC(C)(C)C)C(C)C

Procedure:
According to the general procedure D, from #176 (100 mg, 0.170 mmol, 1 eq.), (S)-1-(tert-butoxycarbonyl)-2-methyl-L-proline (50.7 mg, 0.221 mmol, 1.3 eq.), dichloromethane (4.3 mL), HATU (84.9 mg, 0.221 mmol, 1.3 eq.) and N,N-diisopropylethylamine (0.123 mL, 0.697 mmol, 4.1 eq.), was synthesized the crude desired material, which was purified by silica gel chromatography (Gradient: 0 to 100% ethyl acetate in heptane) to afford #181 (142 mg, assume quantitative yield). LC-MS (Protocol Q1): m/z 800.6 [M+H+], retention time=1.11 minutes.
Reaction SMILES: C(O[C:6](=O)[N:7]([C@H:9]1[CH2:14][CH2:13][C@H:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][N:20]([CH2:22][CH:23]=[CH2:24])[CH3:21])[CH2:11][CH2:10]1)C)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:22]([N:20]([CH3:21])[CH2:19][CH2:18][CH2:17][CH2:16][O:15][C@H:12]1[CH2:13][CH2:14][C@H:9]([NH:7][CH3:6])[CH2:10][CH2:11]1)[CH:23]=[CH2:24]
Reactant: C=CCN(C)CCCCO[C@H]1CC[C@H](N(C)C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CCN(C)CCCCO[C@H]1CC[C@H](NC)CC1

Procedure:
2.1 g (5.9 mmol) trans-(4-[4-(Allyl-methyl-amino)-butoxy]-cyclohexyl)-methyl-carbamic acid tert-butyl ester in 28 ml CH2Cl2 were treated with 6 ml TFA at 0° C. for 1 h, the mixture was concentrated in vacuo and dissolved in EtOAc and saturated aqueous NaHCO3 solution. The phases were separated and the inorganic phase was extracted with EtOAc, the combined organic phases were washed with brine, dried over Na2SO4 and evaporated to yield 1.38 g (91%) trans-(4-[4-(Allyl-methyl-amino)-butoxy]-cyclohexyl)-methyl-amine as yellow oil, MS: 255 (MH+).
Reaction SMILES: [CH2:1]([N:3]([CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:27]C(=O)C)([CH3:26])[CH3:25])[CH2:4][CH2:5][CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:11][CH:10]=1)[OH:8])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CO.O>[CH2:1]([N:3]([CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:27])([CH3:26])[CH3:25])[CH2:4][CH2:5][CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])=[CH:11][CH:10]=1)[OH:8])[CH3:2]
Reactant: CCN(CCCCC(C)(C)OC(C)=O)CCCC(O)c1ccc(NS(C)(=O)=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCN(CCCCC(C)(C)O)CCCC(O)c1ccc(NS(C)(=O)=O)cc1
Reaction time: 24 h
Yield: 35 %

Procedure:
A stirred mixture of the product from Example 25 (0.92 g, 2.08 mmol) and 17.2 mL of a solution of potassium carbonate (5 g) in MeOH (80 mL) and water (20 mL) was refluxed, under nitrogen for 24 h. An additional 17.2 mL of the potassium carbonate solution was added and reflux was continued for 24 h. The mixture was then concentrated to remove MeOH and the aqueous residue was adjusted to pH 8 and washed with EtOAc. The aqueous solution was then concentrated to dryness, and the solid residue was extracted with CH2Cl2. This extract was concentrated and the residue was chromatographed on silica gel with 10% MeOH--1% NH4OH-CHCl3 to give 0.292 g (35.1%) of the titled product, a compound of Formula I': NMR (CDCl3) δ1.09 (t, 3H), 1.21 (s, 6H), 1.53 (m, 9H), 1.97 (m, 1H), 2.55 (m, 6H), 2.94 (s, 3H), 4.61 (m, 1H), 7.15 (d, 2H), 7.35 (d, 2H); MS m/z (relative intensity) 400 (M+, 17.4), 385 (14.5), 367 (11.1), 321 (36.6), 299 (92.8), 172 (100).
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3[N:13]=[C:14]([O:23][CH2:24][C:25]([F:28])([F:27])[F:26])[N:15]=[C:16]([N:17]4[CH2:21][CH2:20][C@H:19]([OH:22])[CH2:18]4)[C:11]=3[N:10]=[N:9]2)=CC=1>C(O)(C(F)(F)F)=O>[F:27][C:25]([F:26])([F:28])[CH2:24][O:23][C:14]1[N:15]=[C:16]([N:17]2[CH2:21][CH2:20][C@H:19]([OH:22])[CH2:18]2)[C:11]2[N:10]=[N:9][NH:8][C:12]=2[N:13]=1
Reactant: COc1ccc(Cn2nnc3c(N4CC[C@H](O)C4)nc(OCC(F)(F)F)nc32)cc1
Solvent: O=C(O)C(F)(F)F
Product: O[C@H]1CCN(c2nc(OCC(F)(F)F)nc3[nH]nnc23)C1

Procedure:
(S)-1-[3-(4-Methoxy-benzyl)-5-(2,2,2-trifluoro-ethoxy)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl]-pyrrolidin-3-ol (example 109, d) in 4.57 mL TFA was heated to 80° C. over night and evaporated. The residue was treated with 1M NaOH and washed with EtOAc. The combined organic layer was evaporated to yield the crude title compound which was used in the consecutive step without further purification. MS (m/e): 305.2 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][S:19][CH2:18][CH2:17]1)[N:9]=[CH:8][N:7]=[C:6]2[O:22]C1C=CC=CC=1.C(=O)([O-])O.[Na+].C(Cl)Cl>Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][S:19][CH2:18][CH2:17]1)[N:9]=[CH:8][NH:7][C:6]2=[O:22]
Reactant: COc1cc2c(Oc3ccccc3)ncnc2cc1OCCN1CCSCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc2c(=O)[nH]cnc2cc1OCCN1CCSCC1
Temperature: 90 °C
Yield: 93.3 %

Procedure:
A mixture of 6-methoxy-4-phenoxy-7-(2-thiomorpholinoethoxy)quinazoline (2.0 g, 5 mmol) in 2M hydrochloric acid (25 ml) was heated at 90° C. for 1.5 hours. The mixture was allowed to cool and adjusted to pH7 with solid sodium hydrogen carbonate. Methylene chloride was added and the resulting semi-solid product was isolated by decanting and filtering the aqueous mixture. This product was dissolved in acetone and insoluble material was removed by filtration. The solvent was removed by evaporation and the residue azeotroped with toluene to give 6-methoxy-7-(2-thiomorpholinoethoxy)-3,4-dihydroquinazolin-4-one (1.5 g, 92%) as a white solid.