Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:14])[C@H:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[NH2:9])([CH3:5])([CH3:4])[CH3:3].C(N(CC)CC)C.[O:22]([CH2:29][C:30](Cl)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1>[CH3:11][C:10]([CH3:13])([CH3:12])[C@H:8]([NH:9][C:30](=[O:31])[CH2:29][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:7]([O:6][C:2]([CH3:5])([CH3:4])[CH3:3])=[O:14]
Reactant: O=C(Cl)COc1ccccc1
Reactant: CC(C)(C)OC(=O)[C@@H](N)C(C)(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)[C@@H](NC(=O)COc1ccccc1)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 79.5 %

Procedure:
A solution of L-tert-Leucine tert-butyl ester hydrochloride (0.20 g, 0.90 mmol) in THF (9 mL) at 0° C. was treated with triethylamine (0.38 mL, 2.73 mmol) and phenoxyacetyl chloride (0.14 mL, 1.01 mmol), stirred at 0° C. for 15 minutes and then at 25° C. for 2 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with brine and dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-10% ethyl acetate/chloroform to give the title compound (0.23 g, 80% yield).
Reaction SMILES: [F:1][C:2]1[CH:16]=[C:15]([N+:17]([O-])=O)[CH:14]=[CH:13][C:3]=1[N:4]([CH2:9][CH:10]([CH3:12])[CH3:11])[CH2:5][CH:6]([CH3:8])[CH3:7].C(Cl)Cl>[Pd].CO>[F:1][C:2]1[CH:16]=[C:15]([NH2:17])[CH:14]=[CH:13][C:3]=1[N:4]([CH2:9][CH:10]([CH3:12])[CH3:11])[CH2:5][CH:6]([CH3:7])[CH3:8]
Reactant: CC(C)CN(CC(C)C)c1ccc([N+](=O)[O-])cc1F
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: CC(C)CN(CC(C)C)c1ccc(N)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.9 %

Procedure:
To a solution of 2-fluoro-N,N-diisobutyl-4-nitroaniline (0.8 g, 3 mmol) in mixed solvents of CH2Cl2 (15 mL) and MeOH (15 mL) was added catalyst Pd/C (80 mg). The reaction mixture was stirred at rt under H2 overnight, and filtered. The filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=8:1) to give the title compound as pale yellow oil (0.40 g, 56%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[C:11]([O:14][CH2:15][CH3:16])(=[O:13])[CH3:12]>N1C=CC=CC=1.[Cu-]=O>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:4]1[CH:3]=[CH:2][CH:10]=[CH:9][C:12]=1[C:11]([O:14][CH2:15][CH3:16])=[O:13])[CH:6]=[CH:5]2
Reactant: Cc1ccc2[nH]ccc2c1
Reactant: CCOC(C)=O
Agent: O=[Cu-]
Solvent: c1ccncc1
Product: CCOC(=O)c1ccccc1-n1ccc2cc(C)ccc21
Temperature: 120 °C

Procedure:
5-Methylindole (730.6 mg, 5.57 mmol, 1.0 eq.) was combined with the title C compound of Example 1 (3.189 g, 13.9 mmole, 2.5 eq.) and copper(I)oxide (797 mg, 5.57 mmol, 1.0 eq.) in pyridine (5.6 ml, 1M). The reaction was heated at 120° C. for 3 hours, cooled to room temperature, diluted with ethyl acetate and filtered through celite. The filtrate was washed twice with water, twice with aqueous 1N hydrochloric acid, and once with aqueous saturated sodium hydrogen carbonate. The organic phase was then dried over sodium sulfate, filtered through magnesium sulfate and concentrated. The residue was chromatographed on silica gel (50 g) eluting with hexane:ether (40:1) followed by (20:1) to give 848 mg of the title A compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1(C)C=CC=CC=1.[Cl:26][C:27]1[CH:38]=[C:31]2[C:32](OC(=O)[NH:36][C:30]2=[CH:29][CH:28]=1)=[O:33]>O1CCCC1>[NH2:36][C:30]1[CH:29]=[CH:28][C:27]([Cl:26])=[CH:38][C:31]=1[C:32]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1)=[O:33]
Reactant: O=c1[nH]c2ccc(Cl)cc2c(=O)o1
Reactant: Nc1ccc(Cl)cn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Nc1ccc(Cl)cc1C(=O)Nc1ccc(Cl)cn1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-amino-5-chloropyridine (787 mg, 6.1 mmol) in tetrahydrofuran (5 ml) was added 0.5M potassium bis(trimethylsilyl)amide in toluene (20 ml, 10.1 mmol) dropwise at −78° C. After stirred for additional 0.5 hr at −78° C., the mixture was added 5-chloroisatoic anhydride (1 g, 5.1 mmol) at −78° C. The mixture was warmed up to r.t gradually and stirred overnight. After concentrated, the crude was washed with saturated ammonium chloride solution and extracted by ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated to give (2-amino-5-chlorophenyl)-N-(5-chloro(2-pyridyl))carboxamide as yellow solid (1.39 g. 99%). MS found for C12H9Cl2N3O M+=282, (M+2)+=284.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>>[C:12]([N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([F:1])[CH:10]=2)[CH2:6][C:7]1=[O:11])(=[O:14])[CH3:13]
Reactant: O=C1Cc2ccc(F)cc2N1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N1C(=O)Cc2ccc(F)cc21
Temperature: 25 °C

Procedure:
82.5 g of 6-fluoro-2-indolinone are stirred in 180 ml acetic anhydride for 3 hours at 130° C. After cooling to ambient temperature the precipitate is suction filtered, washed with 100 ml petroleum ether and dried.
Reaction SMILES: [OH:1][CH2:2][C:3]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[C:4]#[N:5].[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.C(N(CC)CC)C.Cl>ClCCl>[C:4]([C:3]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)([CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:2][O:1][S:23]([C:20]1[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=1)(=[O:25])=[O:24])#[N:5]
Reactant: CCCCCC(C#N)(CO)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCC(C#N)(COS(=O)(=O)c1ccc(C)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 72 %

Procedure:
To a solution containing 4.24 g (19.5 mmol) of 2-hydroxymethyl-2-phenyl-heptanenitrile in 25 mL of dichloromethane are added 4.1 g (21.5 mmol) of p-toluenesulfonyl chloride and 6 mL of triethylamine. The reaction medium is stirred for 15 hours at room temperature and then treated with 1N hydrochloric acid solution and extracted with dichloromethane. The organic phase is dried over sodium sulfate, filtered and evaporated under pressure. A yellow oil is obtained and precipitated from a 9/1 heptane/diisopropyl ether mixture. The precipitate formed is filtered off and rinsed with diisopropyl ether. 5.26 g in the form of a beige-coloured powder are obtained in a yield of 72%.
Reaction SMILES: [CH2:1]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([C:23]3[N:27]([CH3:28])[CH:26]=[N:25][CH:24]=3)([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[OH:16])[CH:13]=2)[N:8]=[C:7](Cl)[C:6]=1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:2][CH2:3][CH3:4].[C:36]([OH:42])([C:38]([F:41])([F:40])[F:39])=[O:37].O(C(C)C)[Na]>CC(O)C>[CH2:1]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([C:23]3[N:27]([CH3:28])[CH:26]=[N:25][CH:24]=3)([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[OH:16])[CH:13]=2)[N:8]=[CH:7][C:6]=1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:2][CH2:3][CH3:4].[C:36]([OH:42])([C:38]([F:41])([F:40])[F:39])=[O:37]
Reactant: CCCCc1c(-c2ccccc2)c(Cl)nc2ccc(C(O)(c3ccncc3)c3cncn3C)cc12
Agent: CC(C)O[Na]
Solvent: CC(C)O
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1c(-c2ccccc2)cnc2ccc(C(O)(c3ccncc3)c3cncn3C)cc12
Temperature: 80 °C

Procedure:
A mixture of (4-butyl-2-chloro-3-phenylquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)pyridin-4-ylmethanol•TFA (16 mg, 0.023 mmol, Example 78) and NaOiPr (19 mg, 0.23 mmol) in iPrOH (0.4 mL) was heated in a sealed tube at 80° C. for 17 hours, and more NaOiPr (7 mg, 0.085 mmol) was added. The mixture was heated for 64 hours and purified by reverse phase HPLC (water/acetonitrile/0.1% TFA) to provide the title compound. 1H NMR (400 MHz, MeOH-d4) δ 9.08 (s, 1H), 8.90 (s, 1H), 8.77 (d, J=6.57 Hz, 3H), 8.29 (d, J=2.02 Hz, 1H), 8.24 (d, J=8.59 Hz, 1H), 8.03 (dd, J=2.02, 9.09 Hz, 1H), 7.83 (d, J=6.57 Hz, 2H), 7.53-7.58 (m, 2H), 7.43 (d, J=6.06 Hz, 2H), 7.18 (s, 1H), 3.72 (s, 3H), 3.06-3.12 (m, 2H), 1.45-1.55 (m, 2H), 1.19-1.28 (m, 2H), 0.78 (t, J=7.33 Hz, 3H); MS m/e 449.2 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:23])[C:9]([C:15]2[CH:16]=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:24])[CH:3]=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][C:27]=1[C:35]([O:37][CH2:38][CH3:39])=[O:36]>>[CH2:38]([O:37][C:35]([C:27]1[CH:28]=[C:29]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH3:23])[C:9]([OH:14])([C:15]3[CH:16]=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:24])[CH:3]=2)[CH:30]=[CH:31][C:26]=1[Cl:25])=[O:36])[CH3:39]
Reactant: CCOC(=O)c1cc(B(O)O)ccc1Cl
Reactant: COc1ccc(C(O)(C(C)c2ccc(Br)cc2Cl)C(F)(F)F)cn1
Product: CCOC(=O)c1cc(-c2ccc(C(C)C(O)(c3ccc(OC)nc3)C(F)(F)F)c(Cl)c2)ccc1Cl

Procedure:
In analogy to Example 150, step 2, 3-(4-bromo-2-chloro-phenyl)-1,1,1-trifluoro-2-(6-methoxy-pyridin-3-yl)-butan-2-ol (Example 175, step 3) was reacted with 4-chloro-3-ethoxycarbonylphenylboronic acid to give the title compound as a colorless foam. MS (m/e)=528.2 [M+H+].
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:21][C:20]3[C:11](=[CH:12][C:13]4[CH2:14][C@@H:15]([C:31](O)=[O:32])[N:16]([C@H:22]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH2:23][CH3:24])[CH2:17][C:18]=4[CH:19]=3)[N:10]([CH3:34])[C:9]2=[O:35])=[CH:4][CH:3]=1.Cl.[CH3:37][O:38][C:39](=[O:56])[C@@H:40]([NH2:55])[CH2:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]2[CH:53]=[CH:52][C:51]([Cl:54])=[CH:50][CH:49]=2)=[CH:44][CH:43]=1>>[CH3:37][O:38][C:39](=[O:56])[C@@H:40]([NH:55][C:31]([C@@H:15]1[CH2:14][C:13]2[CH:12]=[C:11]3[C:20]([O:21][C@@H:8]([C:5]4[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=4)[C:9](=[O:35])[N:10]3[CH3:34])=[CH:19][C:18]=2[CH2:17][N:16]1[C@H:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:23][CH3:24])=[O:32])[CH2:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]2[CH:53]=[CH:52][C:51]([Cl:54])=[CH:50][CH:49]=2)=[CH:44][CH:43]=1
Reactant: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)O)N(C)C(=O)[C@H](c1ccc(O)cc1)O3
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccc(Cl)cc2)cc1
Agent: Cl
Product: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)N[C@@H](Cc1ccc(-c2ccc(Cl)cc2)cc1)C(=O)OC)N(C)C(=O)[C@H](c1ccc(O)cc1)O3

Procedure:
(S)-3-(4′-Chloro-biphenyl-4-yl)-2-{[(3S,7S)-3-(4-hydroxy-phenyl)-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid methyl ester (68 mg, LC/MS: m/z 745) was prepared from (3S,7S)-3-(4-Hydroxy-phenyl)-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylic acid (70 mg) and (S)-2-Amino-3-(4′-chloro-biphenyl-4-yl)-propionic acid methyl ester hydrochloride using general procedure A.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:21].BrC1C=CC=C2C=1C1(C3=CC4OCOC=4C=C3OC1)C(=O)N2.Br[CH2:45][CH2:46][CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49].BrCC1OC(C(F)(F)F)=CC=1>>[O:21]=[C:2]1[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:1]1[CH2:45][CH2:46][CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49]
Reactant: CCOC(=O)CCCBr
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Agent: FC(F)(F)c1ccc(CBr)o1
Agent: O=C1Nc2cccc(Br)c2C12COc1cc3c(cc12)OCO3
Product: CCOC(=O)CCCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21

Procedure:
Following the procedure described in EXAMPLE 10.47, and making non-critical variations using spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 4′-bromospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and ethyl 4-bromobutyrate to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, the title compound was obtained (80%) as a gummy material: 1H NMR (300 MHz, CDCl3) δ 7.29 (t, 1H), 7.14 (d, 1H), 7.04 (d, 1H), 6.99 (d, 1H), 6.48 (s, 1H), 6.18 (s, 1H), 5.84 (d, 2H), 4.76 (ABq, 2H), 4.11 (q, 2H), 3.88-3.71 (m, 2H), 2.40 (t, 2H), 2.03 (t, 2H), 1.21 (t, 3H); 13C NMR (75 MHz, CDCl3) δ 177.4, 172.8, 156.0, 148.9, 142.4, 142.2, 132.4, 129.0, 124.0, 123.3, 119.4, 108.7, 103.0, 101.5, 93.6, 80.5, 60.7, 58.2, 39.6, 31.2, 22.6, 14.3; MS (ES+) m/z 418.08 (M+23), 396.1 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][CH3:17])[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1CCOCC1)C.ClC(OCC(C)C)=O.[CH2:34]([NH:37][C:38]([C@@H:40]1[CH2:48][C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[NH:41]1)=[O:39])[CH2:35][CH3:36]>O1CCCC1.C(Cl)Cl>[CH2:34]([NH:37][C:38]([C@@H:40]1[CH2:48][C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[N:41]1[C:13](=[O:15])[C@@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH2:16][CH3:17])=[O:39])[CH2:35][CH3:36]
Reactant: CCCNC(=O)[C@@H]1Cc2ccccc2N1
Reactant: CC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: CCN1CCOCC1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCCNC(=O)[C@@H]1Cc2ccccc2N1C(=O)[C@H](CC)NC(=O)OCc1ccccc1
Reaction time: 0.75 h

Procedure:
0.439 g (1.85 mmol) of N-benzyloxycarbonyl-2(S)-aminobutyric acid prepared as in Example 3 a) is dissolved, under nitrogen, in tetrahydrofuran (50 ml) and the solution is cooled in an ice/water bath. 0.213 g (1.85 mmol) of N-ethylmorpholine is added, followed by 0.253 g (1.85 mmol) of isobutyl chloroformate. After 45 minutes, 0.378 g (1.85 mmol) of the compound obtained in step b) is added and stirring is continued for 12 hours. The suspension is poured into CH2Cl2 (100 ml) and the mixture is washed with 10% citric acid (3×100 ml) and then with 5% NaHCO3 (3×100 ml). After drying and evaporation, a white solid is obtained which crystallizes from CCl4.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH:14][C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=2)[N:3]=1.[CH2:25]([O:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][NH2:36])=[CH:31][CH:30]=1)[CH:26]=[CH2:27].CCN(C(C)C)C(C)C>C1COCC1>[CH2:25]([O:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][NH:36][C:2]2[N:7]=[C:6]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH:14][C:15]3[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=3)[N:3]=2)=[CH:31][CH:30]=1)[CH:26]=[CH2:27]
Reactant: C=CCOc1ccc(CN)cc1
Reactant: COC(=O)c1ccc(Nc2nc(Cl)nc(OCC(F)(F)F)n2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C=CCOc1ccc(CNc2nc(Nc3ccc(C(=O)OC)cc3)nc(OCC(F)(F)F)n2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 29.6 %

Procedure:
To a suspension of methyl 4-(4-chloro-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoate (500 mg, 1.38 mmol) in THF (5 mL) was added (4-(allyloxy)phenyl)methanamine (275 mg, 1.38 mmol) and iPr2NEt (0.96 mL, 5.51 mmol). The mixture was stirred at room temperature for 16 hours. The solvent was removed under vacuum. The residue was purified via silica gel column (EtOAC/Hexanes=4:1) to give methyl 4-(4-(4-(allyloxy)benzylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoate (0.2 g, 30%) as a white solid.
Reaction SMILES: [S:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2O)[CH:3]=[CH:2]1.O=P(Cl)(Cl)[Cl:13]>ClC(Cl)C>[Cl:13][C:8]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:3]=[CH:2][S:1][C:9]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ccnc2ccsc12
Solvent: CC(Cl)Cl
Product: Clc1ccnc2ccsc12
Reaction time: 2 h
Yield: 74.7 %

Procedure:
A mixture of thieno[3,2-b]pyridin-7-ol (2.50 g, 16.5 mmol) and POCl3 (3.1 mL, 33 mmol) in dichloroethane (10 mL) was stirred for 2 hours at reflux. The mixture was concentrated and the dark residue was resuspended in dichloromethane (50 mL). The solution was carefully neutralized with saturated NaHCO3 solution. The mixture was extracted with dichloromethane, dried over MgSO4, and concentrated to give the title compound (2.09 g, 74%) as a brown solid.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:15][CH:14]=2)=[O:11])[CH:6]=[CH:7][CH:8]=1.[BrH:34]>C(O)(=O)C.C(Cl)(Cl)Cl>[Br:34][CH2:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:15][CH:14]=2)=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: CCCCCCCCCCCCCCOc1ccc(NC(=O)Nc2cccc(CO)c2)cc1
Reactant: Br
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCOc1ccc(NC(=O)Nc2cccc(CBr)c2)cc1

Procedure:
A mixture of 10.0 g of N-[3-(hydroxymethyl)phenyl]-N'-[4-(tetradecyloxy)phenyl]urea, 70 ml of hydrogen bromide in acetic acid and 40 ml of chloroform is refluxed for 2.5 hours, then cooled. The solid is collected and washed with carbon tetrachloride and two times with water. The collected solid is crystallized from ethyl alcohol:tetrahydrofuran followed by recrystallization from tetrahydrofuran to give 7.4 g of the desired product as a white powder, m.p. 164°-169° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)=[CH:3][CH:2]=1.[CH2:17]([O:19][C:20]([C:22]1[NH:23][C:24]([CH:33]=O)=[C:25]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])[C:26]=1[CH3:27])=[O:21])[CH3:18]>>[CH2:17]([O:19][C:20]([C:22]1[NH:23][C:24]([CH:33]=[C:9]2[C:8]3[C:12](=[CH:13][CH:14]=[CH:15][C:7]=3[C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[NH:11][C:10]2=[O:16])=[C:25]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])[C:26]=1[CH3:27])=[O:21])[CH3:18]
Reactant: O=C1Cc2c(cccc2-c2ccncc2)N1
Reactant: CCOC(=O)c1[nH]c(C=O)c(CCC(=O)O)c1C
Product: CCOC(=O)c1[nH]c(C=C2C(=O)Nc3cccc(-c4ccncc4)c32)c(CCC(=O)O)c1C

Procedure:
4-Pyridin-4-yl-1,3-dihydroindol-2-one was condensed with 4-(2-carboxyethyl)-5-formyl-3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester to give the title compound.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH:10]=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.S(=O)(=O)([OH:19])N.Cl([O-])=O.[Na+]>C(O)(=O)C.O>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[C:10]([OH:19])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: NS(=O)(=O)O
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(C(=O)O)cc1OC1CCCC1
Temperature: 20 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
A solution of 3-cyclopentyloxy-4-methoxybenzaldehyde (66 g) and sulfamic acid (39.6 g) in glacial acetic acid (500 mL) is treated dropwise during 1 hour with a solution of sodium chlorite (35 g) in water (150 mL). The mixture is stirred at 20° C. during 1 hour and then it is treated with water (500 mL) dropwise during 30 minutes. The resulting solid is filtered, washed with water and dried, to give 3-cyclopentyloxy-4-methoxybenzoic acid (60.9 g) in the form of white crystals [Elemental analysis: C,65.8; H,6.7%; calculated: C,66.1; H,6.8%].
Reaction SMILES: [F:1][C:2]1[C:3]([N:15]=CN(C)C)=[N:4][C:5](=[O:14])[N:6]([CH:8]2[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9]2)[CH:7]=1.[CH:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][C:29]([N:32]=[C:33]=[O:34])=[CH:28][CH:27]=2)=[CH:22][CH:21]=1>C(Cl)Cl.CN(C)C=O>[NH2:15][C:3]1[C:2]([F:1])=[CH:7][N:6]([CH:8]2[CH2:12][CH2:11][CH:10]([O:13][C:33](=[O:34])[NH:32][C:29]3[CH:28]=[CH:27][C:26]([C:23]4[CH:24]=[CH:25][CH:20]=[CH:21][CH:22]=4)=[CH:31][CH:30]=3)[CH2:9]2)[C:5](=[O:14])[N:4]=1
Reactant: CN(C)C=Nc1nc(=O)n(C2CCC(O)C2)cc1F
Reactant: O=C=Nc1ccc(-c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Nc1nc(=O)n(C2CCC(OC(=O)Nc3ccc(-c4ccccc4)cc3)C2)cc1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 38.2 %

Procedure:
A solution of N′-[5-fluoro-1-(3-hydroxy-cyclopentyl)-2-oxo-1,2-dihydro-pyrimidin-4-yl]-N,N-dimethyl-formamidine (0.050 g, 0.186 mmol) in CH2Cl2 (2 mL) and anhydrous dimethylformamide (1 mL) was treated with 4-biphenyl isocyanate (0.039 g, 0.2 mmol). The mixture was stirred at room temperature under nitrogen for 5 hours, then quenched by the addition of acetic acid (0.5 mL) and stirred 10 minutes. The mixture was concentrated in vacuo, loaded on silica gel, and chromatographed on silica gel (10 g SiO2, 8:1 ethyl acetate/methanol) to afford biphenyl-4-yl-carbamic acid 3-(4-amino-5-fluoro-2-oxo-2H-pyrimidin-1-yl)-cyclopentyl ester 31 as a white solid (0.029 g, 38%).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:5]=[CH:6][C:7]=1[CH:8]([OH:14])[C:9]([O:11]CC)=[O:10].NC1C=CC(C2C=CC(C(O)C(OCC)=[O:36])=CC=2)=CC=1.OC1C=C(C2C=CC=CC=2)C=CC=1C(O)C(O)=O.OC1C=CC(C2C=CC(C(O)C(O)=O)=CC=2)=CC=1>>[OH:36][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:4]1[CH:5]=[CH:6][C:7]([CH:8]([OH:14])[C:9]([OH:11])=[O:10])=[CH:2][CH:3]=1
Reactant: CCOC(=O)C(O)c1ccc(-c2ccc(N)cc2)cc1
Reactant: CCOC(=O)C(O)c1ccc(-c2ccccc2)cc1N
Agent: O=C(O)C(O)c1ccc(-c2ccc(O)cc2)cc1
Agent: O=C(O)C(O)c1ccc(-c2ccccc2)cc1O
Product: O=C(O)C(O)c1ccc(-c2ccccc2O)cc1

Procedure:
When ethyl 3-amino-4-biphenylylglycolate or ethyl 4'-amino-4-biphenylylglycolate are used in the above procedure then the product prepared is 3-hydroxy-4-biphenylylglycolic acid or 4'-hydroxy-4-biphenylylglycolic acid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([OH:13])[CH2:10][CH:9]1[CH2:14][OH:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:16][S:17](Cl)(=[O:19])=[O:18]>N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([O:13][S:17]([CH3:16])(=[O:19])=[O:18])[CH2:10][C@@H:9]1[CH2:14][O:15][S:17]([CH3:16])(=[O:19])=[O:18])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC(O)CC1CO
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1C[C@@H](OS(C)(=O)=O)C[C@@H]1COS(C)(=O)=O
Reaction time: 16 h

Procedure:
To a solution of 4-hydroxy-2-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (10.85 g, 50.0 mmol) in pyridine (50 mL) was added methanesulfonyl chloride (10.8 mL, 140 mmol) over a period of 20 min. After stirring for 16 h, the reaction mixture was concentrated to dryness, diluted with satd. aq. Na2CO3 and extracted with EtOAc (2×). The combined organic layers were dried (MgSO4), filtered and concentrated to provide the title compound as an oil that slowly solidified (14.4 g, 84%). 1H NMR (400 MHz, CDCl3): 5.24-5.20 (m, 1H), 4.72-4.47 (m, 1H), 4.32-4.17 (m, 2H), 4.01-3.75 (m, 1H), 3.63-3.48 (m, 1H), 3.04 (s, 3H), 3.01 (s, 3H), 2.60-2.25 (m, 2H), 1.48 (s, 9H).
Reaction SMILES: Cl[CH2:2][C:3]1[N:12]=[C:11]([N:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH3:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[NH:23]1[CH2:27][CH2:26][CH2:25][C:24]1=[O:28].C([Li])CCC.COC1C=CC(CNC2C3C(=CC=CC=3)N=C(CN3CCCCC3=O)N=2)=CC=1>C1COCC1>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([N:13]([CH3:14])[C:11]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[N:4]=[C:3]([CH2:2][N:23]3[CH2:27][CH2:26][CH2:25][C:24]3=[O:28])[N:12]=2)=[CH:16][CH:17]=1
Reactant: COc1ccc(N(C)c2nc(CCl)nc3ccccc23)cc1
Reactant: O=C1CCCN1
Agent: COc1ccc(CNc2nc(CN3CCCCC3=O)nc3ccccc23)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(N(C)c2nc(CN3CCCC3=O)nc3ccccc23)cc1

Procedure:
The title compound was prepared from (2-chloromethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (150 mg, 0.43 mmol), 2-pyrrolidinone (128 mg, 1.5 mmol) and n-butyllithium (2.5 M in THF, 1.2 mL, 3 mmol) in THF (2 mL) by a procedure similar to the preparation of 1-{4-[(4-methoxyphenyl)methylamino]quinazolin-2-ylmethyl}piperidin-2-one in Example 252 and was isolated as a yellow solid. 1H NMR (CDCl3) δ 7.75-7.73 (m, 1H), 7.55-7.51 (m, 1H), 7.13-7.10 (d, 2H), 6.99-6.97 (m, 2H), 6.93-6.90 (d, 2H), 4.72 (s, 2H), 3.84 (s, 3H), 3.61 (t, 2H), 3.54 (s, 3H), 2.53 (t, 2H), 2.15-2.10 (pentet, 2H); LC-MS (ESI+; 363 ([M+H]+)).