Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[N:6]2[CH2:7][CH2:8][N:9]([C:11]([O:13]C(C)(C)C)=O)[CH2:10][CH:5]2[CH:4]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:3]1.FC(F)(F)C(O)=O.O1CCCC1.[F:36][C:37]1[CH:42]=[CH:41][C:40]([N:43]=C=O)=[CH:39][CH:38]=1>ClCCl>[F:36][C:37]1[CH:42]=[CH:41][C:40]([NH:43][C:11]([N:9]2[CH2:8][CH2:7][N:6]3[C:2](=[O:1])[O:3][CH:4]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:5]3[CH2:10]2)=[O:13])=[CH:39][CH:38]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCN2C(=O)OC(c3ccccc3)C2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: O=C(Nc1ccc(F)cc1)N1CCN2C(=O)OC(c3ccccc3)C2C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 18.8 %

Procedure:
To a solution of 1,1-dimethylethyl tetrahydro-3-oxo-1-phenyl-3H-oxazolo[3,4-a]pyrazine-7(1H)-carboxylate (94 mg, 0.30 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (0.5 mL), and the mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated, and then ethyl acetate was added to the residue. The resulting mixture was washed with a 0.5 M aqueous sodium hydrogen carbonate solution (50 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To the residue were added tetrahydrofuran (5 mL) and 4-fluorophenyl isocyanate (0.10 g, 0.73 mmol), and the mixture was stirred at 50° C. for 1 hour. The reaction solution was concentrated, and then the residue was purified with silica gel column chromatography (hexane:ethyl acetate=1:1 to ethyl acetate) to obtain the title compound (20 mg, yield 19%) as a diastereomer mixture. Diastereomer ratio (α:β=3:1).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[C:7]([CH:9]=1)[NH2:8].[C:16](#[N:20])[CH:17]([CH3:19])[CH3:18].[Cl-].[Al+3].[Cl-].[Cl-]>>[CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[C:7]([NH:8][C:16](=[NH:20])[CH:17]([CH3:19])[CH3:18])[CH:9]=1
Reactant: CSc1ccc(N2CCOCC2)c(N)c1
Reactant: CC(C)C#N
Agent: [Al+3]
Agent: [Cl-]
Product: CSc1ccc(N2CCOCC2)c(NC(=N)C(C)C)c1
Temperature: 140 °C

Procedure:
A mixture of 5-methylthio-2-morpholinoaniline (1.8 g), isobutyronitrile (1.66 g) and anhydrous aluminium chloride (3.2 g) was heated at 140° C. for 2 hours to give N-(5-methylthio-2-morpholinophenyl) isobutyramidine (m.p. 155° C.) which was recrystallised from hexane.
Reaction SMILES: CC([O:5][C:6](=[O:29])[CH:7]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:8]([O:10]C(C)(C)C)=[O:9])(C)C.CC([O-])(C)C.[K+].[C:36]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)(=[O:39])[CH:37]=[CH2:38].CC(O)=O>CC(O)(C)C>[CH2:41]([O:40][C:36](=[O:39])[CH2:37][CH2:38][C:7]([C:8]([OH:10])=[O:9])([C:6]([OH:5])=[O:29])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: CCCCCCCCCCCCCCC(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: C=CC(=O)OCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CC(C)(C)O
Product: CCCCCCCCCCCCCCC(CCC(=O)OCc1ccccc1)(C(=O)O)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 49.9 %

Procedure:
To a solution of di-(dimethylethyl)-n-tetradecylmalonate 34 (4.12 g, 10.0 mmol) and t-BuOK (244 mg, 2.0 mmol) in t-BuOH (10 mL, dried over 4 Å sieves) was added a solution of benzyl acrylate (1.62 g, 10.0 mmol in 5 mL t-BuOH). The initially colorless solution immediately turned brown. It was stirred (3 h, rt) then additional t-BuOK (112 mg, 1.0 mmol) was added and the reaction continued overnight. The mixture was neutralized with AcOH then evaporated to dryness and treated with neat TFA (20 mL, 1 h). The TFA was removed by rotary evaporation, the residue dissolved in warm hexane, treated with activated charcoal then filtered. The filtrate provided fine white crystals which proved to be pasty when filtered. Drying provided product 36 as a white solid (2.31 g, 50%), mp 47°-49° C. High resolution FAB MS:C27H43O6 (M+H); Theor. 463.307147. Found 463.3059 646. Anal. C27H42O6.1/2H2O:C,H.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]([F:26])([F:25])[C:8]([C:14]1[CH:23]=[C:18]([C:19]([O:21][CH3:22])=[O:20])[C:17]([NH2:24])=[CH:16][CH:15]=1)([OH:13])[C:9]([F:12])([F:11])[F:10].O>N1C=CC=CC=1>[F:6][C:7]([F:25])([F:26])[C:8]([C:14]1[CH:15]=[CH:16][C:17]([NH:24][S:2]([CH3:1])(=[O:4])=[O:3])=[C:18]([C:19]([O:21][CH3:22])=[O:20])[CH:23]=1)([OH:13])[C:9]([F:10])([F:12])[F:11]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1N
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)c1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1NS(C)(=O)=O
Reaction time: 8 h

Procedure:
Add 2.50 g (22 mmole) of methanesulfonyl chloride dropwise to 4.57 g (15 mmole) of methyl 5-(hexafluoro-2-hydroxy-2-propyl)anthranilate in 25 ml of pyridine and allow to stand overnight. Pour the reaction into H2O and extract with Et2O. Wash the Et2O with 1N HCl and extract with 1N NaOH. Acidify the NaOH and extract with Et2O. Dry, concentrate and recrystallize from Et2O-hexane to obtain 4'-(hexafluoro-2-hydroxy-2-propyl)-2'-(methoxycarbonyl)methanesulfonanilide; m.p. 147°-148° C.
Reaction SMILES: FC1C=C(C2N=C(SC)N=C(N3CCOC[C@@H]3C)C=2)C=NC=1.Cl[C:24]1[CH:29]=[C:28]([C:30]2[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=2[S:37][CH3:38])[N:27]=[C:26]([S:39][CH3:40])[N:25]=1.[OH:41][CH2:42][CH2:43][NH:44][C:45]([NH:47][C:48]1[CH:53]=[CH:52][C:51](B2OC(C)(C)C(C)(C)O2)=[CH:50][CH:49]=1)=[O:46]>>[F:36][C:34]1[CH:33]=[CH:32][C:31]([S:37][CH3:38])=[C:30]([C:28]2[N:27]=[C:26]([S:39][CH3:40])[N:25]=[C:24]([C:51]3[CH:52]=[CH:53][C:48]([NH:47][C:45]([NH:44][CH2:43][CH2:42][OH:41])=[O:46])=[CH:49][CH:50]=3)[CH:29]=2)[CH:35]=1
Reactant: CC1(C)OB(c2ccc(NC(=O)NCCO)cc2)OC1(C)C
Reactant: CSc1nc(Cl)cc(-c2cc(F)ccc2SC)n1
Agent: CSc1nc(-c2cncc(F)c2)cc(N2CCOC[C@@H]2C)n1
Product: CSc1nc(-c2ccc(NC(=O)NCCO)cc2)cc(-c2cc(F)ccc2SC)n1

Procedure:
Method as described for intermediate 5 using 4-chloro-6-(5-fluoro-2-(methylthio)phenyl)-2-(methylthio)pyrimidine and 1-(2-hydroxyethyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (intermediate 18). Reaction mixture was partitioned between DCM and water, the organic phase passed through a PTFE hydrophobic frit and the solvent removed in vacuo. The residue was purified further by flash chromatography (40-100% EtOAc in petroleum ether (40:60) followed by 0-15% MeOH in petroleum ether (40:60) to afford 1-(4-(6-(5-fluoro-2-(methylthio)phenyl)-2-(methylthio)pyrimidin-4-yl)phenyl)-3-(2-hydroxyethyl)urea as a brown solid, (200 mg, 54%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([OH:12])=O)[CH:3]=[CH:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:44]([C:48]1[CH:63]=[CH:62][C:51]([CH2:52][NH:53][CH2:54][CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)=[CH:50][CH:49]=1)([CH3:47])([CH3:46])[CH3:45]>CN(C=O)C.O>[C:44]([C:48]1[CH:63]=[CH:62][C:51]([CH2:52][N:53]([CH2:54][CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[C:10]([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[NH:1][CH:2]=[CH:3]3)=[O:12])=[CH:50][CH:49]=1)([CH3:47])([CH3:45])[CH3:46]
Reactant: O=C(O)c1cccc2cc[nH]c12
Reactant: CC(C)(C)c1ccc(CNCCc2ccccc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccc(CN(CCc2ccccc2)C(=O)c2cccc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 81.2 %

Procedure:
To a solution of 48 mg (0.3 mmol) of 1H-indole-7-carboxylic acid and 96 mg of TBTU (0.3 mmol) in 4 ml DMF, were added 0.26 ml (1.5 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 80 mg (0.3 mmol) of (4-tert-butyl-benzyl)-phenethyl-amine in 1 ml DMF were added. After stirring for 5 h at rt, the reaction mixture was diluted with 50 ml water and extracted with 2×50 ml EtOAc. The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (8 g silica gel; EtOAc/heptane 1:6) to give 100 mg white solid (80%). MS (ISP) 411.5 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[C:7]([CH:10]=1)[C:8]#[N:9].Cl[C:23]1[CH:33]=[C:27]2[N:28]([CH3:32])[CH2:29][CH2:30][CH2:31][N:26]2[C:25](=[O:34])[N:24]=1>>[CH3:32][N:28]1[CH2:29][CH2:30][CH2:31][N:26]2[C:25](=[O:34])[N:24]=[C:23]([O:1][CH2:2][C:3]3[CH:4]=[CH:5][C:6]([O:11][C:12]4[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:14][CH:13]=4)=[C:7]([CH:10]=3)[C:8]#[N:9])[CH:33]=[C:27]12
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Reactant: N#Cc1cc(CO)ccc1Oc1ccc(C(F)(F)F)cc1
Product: CN1CCCn2c1cc(OCc1ccc(Oc3ccc(C(F)(F)F)cc3)c(C#N)c1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E2 starting from 5-(hydroxymethyl)-2-(4-(trifluoromethyl)phenoxy)benzonitrile and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: [CH2:1]([Li])CCC.C(NC(C)C)(C)C.[C:13]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:18]=[CH:17][C:16]([CH2:19][C@H:20]2[N:24]([C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])[C:23](=[O:31])[CH2:22][CH2:21]2)=[CH:15][CH:14]=1.COS(OC)(=O)=O>O1CCCC1.[Cl-].[NH4+]>[C:13]1([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:14]=[CH:15][C:16]([CH2:19][C@H:20]2[N:24]([C:25](=[O:30])[C:26]([CH3:28])([CH3:29])[CH3:27])[C:23](=[O:31])[C@H:22]([CH3:1])[CH2:21]2)=[CH:17][CH:18]=1
Reactant: [Li]CCCC
Reactant: CC(C)(C)C(=O)N1C(=O)CC[C@H]1Cc1ccc(-c2ccccc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: COS(=O)(=O)OC
Solvent: C1CCOC1
Product: C[C@@H]1C[C@@H](Cc2ccc(-c3ccccc3)cc2)N(C(=O)C(C)(C)C)C1=O
Reaction time: 0.25 h

Procedure:
0.37 ml of n-butyllithium (1.6 M) was added to a solution of 88 μl diisopropylamine in 1 ml tetrahydrofuran at about 0° C. After about 15 min, 200 mg (S)-5-biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)pyrrolidin-2-one (1-a, R1=pivaloyl) of example 4 dissolved in 2 ml tetrahydrofuran were added. After about 15 min, 59 μl dimethylsulphate were added. After about 2 hours at about 0° C., the mixture was diluted with ammonium chloride solution, extracted with ethyl acetate and concentrated to dryness (196 mg). According to HNMR analysis, the ratio of diastereoisomers is 83:17 [(3R,5S): (3S,5S)]. The material was purified by chromatography to afford 43 mg (3R,5S)-5-biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)-3-methylpyrrolidin-2-one=1H-NMR (DMSO): (2-a, R1=pivaloyl) 1.07 (3H, d, 1-CH3); 1.29 (9H, s, C(CH3)3); 1.63 (1H, m, 4-CHH); 2.03 (1H, m, 4-CHH); 2.81 (2H, m, 3-CH, 1-CHH); 2.94 (1H, dd, 1-CHH); 4.45 (1H, m, 5-CH); 7.34 (3H, m, aromatic); 7.44 (2H, m, aromatic); 7.61 (4H, m, aromatic). m/z: 350 (MH+, 100%). Spectroscopic data for (2-b, R1=pivaloyl) as Example 5-2.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]=[O:13])[CH:7]=1)(=[O:4])=[O:3].[CH3:14][C:15](=[N:19]O)[C:16](=O)[CH3:17].[ClH:21].C(OCC)(=O)C>>[CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[O:13][C:16]([CH3:17])=[C:15]([CH2:14][Cl:21])[N:19]=2)[CH:7]=1)(=[O:4])=[O:3]
Reactant: CC(=O)C(C)=NO
Reactant: Cl
Reactant: CS(=O)(=O)Oc1cccc(C=O)c1
Solvent: CCOC(C)=O
Product: Cc1oc(-c2cccc(OS(C)(=O)=O)c2)nc1CCl
Temperature: 25 °C
Reaction time: 120 h

Procedure:
A mixture of 3-formylphenyl methanesulfonate (41.40 g), 2,3-butanedione-2-oxime (20.91 g) and 4N hydrogenchloride-ethyl acetate solution (250 mL) was stirred at room temperature for 5 days. After concentration of the reaction mixture, the residue was decanted and washed with diethyl ether. To the obtained residue was added tetrahydrofuran (300 mL), and thionyl chloride (37.00 g) was further added. The mixture was heated under reflux for 3 hrs. The reaction mixture was concentrated and ethyl acetate was added to the residue. The ethyl acetate layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography. 3-(4-Chloromethyl-5-methyl-1,3-oxazol-2-yl)phenyl methanesulfonate from the eluted portion of ethyl acetate-hexane (1:3 to 1:1, v/v) was obtained as colorless crystals (34.29 g, 55%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 102-103° C.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[H-].[Na+].Cl[S:7]([CH:10]1[CH2:15][CH2:14][N:13](C(OCC2C=CC=CC=2)=O)[CH2:12][CH2:11]1)(=[O:9])=[O:8].O>CN(C)C=O>[CH3:1][N:2]([CH3:3])[S:7]([CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)(=[O:9])=[O:8]
Reactant: CNC
Reactant: O=C(OCc1ccccc1)N1CCC(S(=O)(=O)Cl)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)S(=O)(=O)C1CCNCC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 133.3 %

Procedure:
A suspension of an amine such as dimethylamine (4.72 mmol) and sodium hydride (4.72 mmol) in N,N-dimethylformamide (10 ml) was stirred for five minutes at room temperature. Then phenylmethyl 4-(chlorosulfonyl)-1-piperidinecarboxylate (1.60 mmol) was added to the reaction mixture and stirred at 100° C. for 3 hours. The reaction mixture was poured into water (25 ml) and extracted with ethyl acetate (3×25 ml). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated to give the title compound (410 mg, 80% yield) as an off-white solid. MS(ES)+ m/e 327.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])[N:5]=[CH:4][N:3]=1.[CH2:15]([OH:20])[C:16]#[C:17][CH2:18][CH3:19].[H-].[Na+].O>CN(C)C=O>[F:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[CH:7]=[C:2]([O:20][CH2:15][C:16]#[C:17][CH2:18][CH3:19])[N:3]=[CH:4][N:5]=1
Reactant: CCC#CCO
Reactant: Fc1ccccc1-c1cc(Cl)ncn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC#CCOc1cc(-c2ccccc2F)ncn1
Temperature: 25 °C
Reaction time: 6 h
Yield: 73.3 %

Procedure:
In 10 ml of N,N-dimethylformamide were dissolved 522 mg of 4-chloro-6-(2-fluorophenyl)pyrimidine and 231 mg of 2-pentyn-1-ol, to which 110 mg of sodium hydride (60% in oil) was added, followed by stirring at room temperature for 6 hours. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The resulting residue was subjected to silica gel column chromatography to give 470 mg of 4-(2-fluorophenyl)-6-(2-pentynyloxy)pyrimidine (the present compound (86)).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[O:6][CH:7]1[CH2:10][NH:9][CH2:8]1.[CH:16]([N:19]=[C:20]=[O:21])([CH3:18])[CH3:17]>C(Cl)Cl>[CH3:17][CH:16]([NH:19][C:20]([N:9]1[CH2:10][CH:7]([O:6][C:5]2[CH:11]=[CH:12][CH:13]=[C:3]([C:2]([F:1])([F:14])[F:15])[CH:4]=2)[CH2:8]1)=[O:21])[CH3:18]
Reactant: CC(C)N=C=O
Reactant: FC(F)(F)c1cccc(OC2CNC2)c1
Solvent: ClCCl
Product: CC(C)NC(=O)N1CC(Oc2cccc(C(F)(F)F)c2)C1
Yield: 39.4 %

Procedure:
To a stirred and chilled (10°-20° C.) solution of 9.0 g (0.042 mole) of 3-[3-(trifluoromethyl)phenoxy]azetidine in 100 ml of dry methylene chloride was added dropwise 4.1 g (0.048 mole) of isopropyl isocyanate. The reaction mixture was stirred at room temperature for 2 hr and was diluted with 100 ml of methylene chloride. The solution was washed with 5% sodium hydroxide (2×40 ml), water (50 ml), saturated sodium chloride (50 ml), dried (sodium sulfate) and concentrated in vacuo. The residue was crystallized from ethyl acetate, affording 7.6 g (60.6%). Recrystallization from ethyl acetate gave 5.0 g of clear white needles, m.p. 150°-151.5° C.
Reaction SMILES: [CH3:1][NH2:2].[CH3:3][O:4][C:5]1[C:10]2[C:11](=O)[O:12]C(=O)[NH:14][C:9]=2[CH:8]=[CH:7][CH:6]=1>O.CCOC(C)=O>[NH2:14][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]([O:4][CH3:3])[C:10]=1[C:11]([NH:2][CH3:1])=[O:12]
Reactant: COc1cccc2[nH]c(=O)oc(=O)c12
Reactant: CN
Solvent: CCOC(C)=O
Solvent: O
Product: CNC(=O)c1c(N)cccc1OC
Temperature: 25 °C
Reaction time: 36 h
Yield: 70.1 %

Procedure:
Phosgene (4.72 ml, 8.97 mmol; 20% in toluene) was added dropwise to a solution of 2-amino-6-methoxybenzoic acid (1 g, 5.98 mmol) in 2N aqueous sodium hydroxide (6.28 ml, 12.56 mmol) and water (15 ml) cooled to 0° C. over a period of 15 minutes, maintaining the temperature at 0-5° C. The resulting suspension was stirred at 0° C. for 15 minutes. The precipitate was collected by filtration, washed with water, followed by a small amount of acetonitrile and ether and dried under vacuum at 40° C. to afford 5-methoxy-1H-3,1-benzoxazine-2,4-dione (0.760 g, 65.8%) as a beige solid. 40% aqueous methylamine (1.57 ml, 18.1 mmol) was added to a stirred suspension of 5-methoxy-1H-3,1-benzoxazine-2,4-dione (700 mg, 3.62 mmol;) in water (5 ml). The resulting solution was stirred at room temperature for 36 hours. The mixture was diluted with EtOAc, washed sequentially with saturated aqueous sodium carbonate, water and brine. The organic layer was dried over MgSO4 and evaporated to afford 2-amino-6-methoxy-N-methylbenzamide (457 mg, 70.0%) as a white solid. 1H NMR spectrum (500 MHz, DMSO): 2.73 (d, 3H), 3.73 (s, 3H), 5.79 (bs, 2H), 6.19 (d, 1H), 6.30 (d, 1H), 6.99 (dd, 1H), 7.98 (q, 1H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[O:19]C)[N:3]=1.C(OC(N1CCCCC(N)C1)=O)(C)(C)C.C(OC([N:43]1[CH2:49][CH2:48][CH2:47][CH:46]([NH2:50])[CH2:45][CH2:44]1)=O)(C)(C)C>>[NH:43]1[CH2:49][CH2:48][CH2:47][CH:46]([NH:50][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([C:12]3[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=3[OH:19])[N:3]=2)[CH2:45][CH2:44]1
Reactant: COc1ccc(Cl)cc1-c1nc(Cl)c2ccccc2n1
Reactant: CC(C)(C)OC(=O)N1CCCC(N)CC1
Agent: CC(C)(C)OC(=O)N1CCCCC(N)C1
Product: Oc1ccc(Cl)cc1-c1nc(NC2CCCNCC2)c2ccccc2n1

Procedure:
The title compound was prepared using a method analogous to that described in Synthesis 52, replacing 4-chloro-2-(2-methoxyphenyl)quinazoline with 4-chloro-2-(5-chloro-2-methoxyphenyl)quinazoline in Synthesis 52-A and tert-butyl-3-aminoazepane-1-carboxylate with tert-butyl-4-aminoazepane-1-carboxylate in Synthesis 52-B.
Reaction SMILES: [CH3:1][N:2]([C:11](OC(C)(C)C)=O)[C@H:3]([C:8]([OH:10])=[O:9])[CH2:4][CH:5]([CH3:7])[CH3:6].CN(C(ON1N=NC2C=C[CH:31]=[CH:32][C:27]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:42](N(C(C)C)CC)(C)C>CC#N>[CH3:7][CH:5]([CH3:6])[CH2:4][C@H:3]([N:2]([CH3:1])[CH2:11][CH:42]=[C:32]([CH3:31])[CH3:27])[C:8]([OH:10])=[O:9]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Product: CC(C)=CCN(C)[C@@H](CC(C)C)C(=O)O
Yield: 340.9 %

Procedure:
A mixture of Ia (0.535 g, 1.65 mmol), N-Methyl-N-Boc-L-Leucine (0.405 g, 1.65 mmol), HBTU (0.625 g, 1.65 mmol), and diisopropylethylamine (0.516 g, 6.6 mmol) was stirred in CH3CN (30 mL) for 15 hours. The reaction mixture was concentrated, redissolved in EtOAc, washed 3 times with saturated sodium bicarbonate solution and once with brine, then concentrated to give 1.2 g of the desired product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[N:7]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([CH:18]=O)[CH:12]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[CH:28]1([NH2:31])[CH2:30][CH2:29]1.[BH4-].[Na+].C([O-])(O)=O.[Na+]>CO>[C:1]([O:5][C:6](=[O:20])[N:7]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([CH2:18][NH:31][CH:28]2[CH2:30][CH2:29]2)[CH:12]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(CCc1ccc(Cl)c(C=O)c1)C(=O)OC(C)(C)C
Reactant: NC1CC1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Product: CN(CCc1ccc(Cl)c(CNC2CC2)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.4 %

Procedure:
A mixture of [2-(4-chloro-3-formyl-phenyl)-ethyl]-methyl-carbamic acid tert-butyl ester (325 mg, 1.09 mmol), Et3N (0.228 mL, 1.64 mmol) and cyclopropylamine (0.115 mL, 1.64 mmol) in MeOH (3.66 mL) was heated to reflux for 4 h. The mixture was allowed to cool to rt, and NaBH4 (103 mg, 2.73 mmol) was added. The mixture was stirred for 1 h at rt, and aq. sat. NaHCO3 was added. The mixture was extracted with EtOAc several times. The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC yielded the title compound (186 mg, 50%). LC-MS: tR=0.79 min; ES+: 339.39.
Reaction SMILES: NC(N)=S.[CH3:5][N:6]([CH3:19])[S:7]([C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[C:12]([NH2:17])[C:11]=1[OH:18])(=[O:9])=[O:8].[CH3:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]=[C:28]=[S:29]>>[Cl:16][C:15]1[CH:14]=[CH:13][C:12]([NH:17][C:28]([NH:27][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[CH3:20])=[S:29])=[C:11]([OH:18])[C:10]=1[S:7]([N:6]([CH3:19])[CH3:5])(=[O:9])=[O:8]
Reactant: CN(C)S(=O)(=O)c1c(Cl)ccc(N)c1O
Reactant: Cc1ccccc1N=C=S
Agent: NC(N)=S
Product: Cc1ccccc1NC(=S)Nc1ccc(Cl)c(S(=O)(=O)N(C)C)c1O
Yield: 69.6 %

Procedure:
Following the general procedure for thiourea formation outlined in example 12, N,N-dimethyl-3-amino-6chloro-2-hydroxybenzenesulfonamide (500 mg, 2 mmol) and 2-methylphenylisothiocyanate (298.4 mg, 2 mmol) were coupled to form the desired thiourea (557 mg, 70%). EI-MS m/z 400.0 (M30 ).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[CH:7][N:6]=[C:5]2[NH:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=1.[Cl:22][CH2:23][C:24](Cl)=[O:25]>>[ClH:12].[Cl:12][C:11]1[CH:10]=[C:9]2[C:4]([C:5]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=3)=[N:6][CH:7]=[N:8]2)=[CH:3][C:2]=1[NH:1][C:24](=[O:25])[CH2:23][Cl:22]
Reactant: Nc1cc2c(Nc3ccc(Cl)c(Cl)c3)ncnc2cc1Cl
Reactant: O=C(Cl)CCl
Product: Cl
Product: O=C(CCl)Nc1cc2c(Nc3ccc(Cl)c(Cl)c3)ncnc2cc1Cl
Yield: 76 %

Procedure:
Using an analogous procedure to that described in Example 4, 6-amino-7-chloro-4-(3',4'-dichloroanilino)quinazoline was reacted with 2-chloroacetyl chloride to give 7-chloro-6-(2-chloroacetamido)-4-(3',4'-dichloroanilino)quinazoline hydrochloride in 76% yield, m.p.>280° C.;
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:20][C@H:21]([C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1)[CH3:22]>>[F:1][C:2]1[CH:10]=[C:6]([C:7]([NH:20][C@H:21]([C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=2)[CH3:22])=[O:9])[C:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[N:4][CH:3]=1
Reactant: O=C(O)c1cc(F)cnc1Cc1ccc(F)cc1
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(F)cnc2Cc2ccc(F)cc2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 5-fluoro-2-(4-fluorobenzyl)nicotinic acid (step 3 of Example 58) and methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride (step 3 of Example 5): 1H-NMR (CDCl3) δ 9.13 (1H, d, J=7.7 Hz), 8.59 (1H, d, J=3.0 Hz), 7.93 (2H, d, J=8.4 Hz), 7.79 (1H, dd, J=8.7, 2.8 Hz), 7.51 (2H, d, J=8.2 Hz), 7.15–7.09 (2H, m), 7.03–6.96 (2H, m), 5.19–5.09 (1H, m), 4.17 (1H, d, J=13.7 Hz), 4.08 (1H, d, J=13.7 Hz), 3.85 (3H, s), 1.42 (3H, d, J=7.1 Hz); MS (ESI) m/z 411 (M+H)+, 409 (M−H)−.