Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:24]=[C:23]([C:25]([NH:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([OH:35])[CH:30]=2)=[O:26])[CH:22]=[CH:21][C:3]=1[C:4]([NH:6][C@H:7]([C:17]([O:19]C)=[O:18])[CH2:8][NH:9][C:10]([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)=[O:11])=[O:5].[OH-].[Na+]>CO.ClCCl>[Br:1][C:2]1[CH:24]=[C:23]([C:25]([NH:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([OH:35])[CH:30]=2)=[O:26])[CH:22]=[CH:21][C:3]=1[C:4]([NH:6][C@H:7]([C:17]([OH:19])=[O:18])[CH2:8][NH:9][C:10]([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)=[O:11])=[O:5]
Reactant: COC(=O)[C@H](CNC(=O)c1cccs1)NC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: O=C(NCc1cccc(O)c1)c1ccc(C(=O)N[C@@H](CNC(=O)c2cccs2)C(=O)O)c(Br)c1
Reaction time: 24 h
Yield: 75.7 %

Procedure:
To a solution of N-[2-bromo-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-3-(thiophene-2-carbonyl)amino-L-alanine methyl ester (Example 306; 195 mg, 0.348 mmol) in methanol (2 mL) at 25° C. was added 1 N NaOH (350 μL, 0.348 mmol). The reaction mixture was stirred for 24 h and TLC (10% methanol in dichloromethane) revealed that starting material was still present. 1 N NaOH (350 μL) was added at room temperature and the reaction was stirred for 24 h. The solvents were evaporated under reduced pressure, the residue was placed under vacuum for 1 h, and then purified by HPLC (gradient of acetonitrile, water, 0.075% TFA). The pure fractions were combined, concentrated under vacuum and then freeze dried for 24 h to yield N-[2-bromo-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-3-(thiophene-2-carbonyl)amino-L-alanine (144 mg, 76%) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH3:7])[N:4]=[C:3]1[CH2:8]O.Cl.[NH2:11][CH2:12][CH2:13][SH:14].[BrH:15]>>[BrH:15].[BrH:15].[CH3:1][N:2]1[CH:6]=[C:5]([CH3:7])[N:4]=[C:3]1[CH2:8][S:14][CH2:13][CH2:12][NH2:11]
Reactant: Cc1cn(C)c(CO)n1
Reactant: NCCS
Agent: Br
Agent: Cl
Product: Cc1cn(C)c(CSCCN)n1

Procedure:
The reaction of 1,4-dimethyl-2-hydroxymethylimidazole (2.5 g.) with cysteamine hydrochloride (2.5 g.) in aqueous hydrobromic acid by the method described in Example 1 (i) (a) gave 1,4-dimethyl-2-[(2-aminoethyl)thiomethyl]imidazole dihydrobromide (6.2 g.) m.p. 161°-163° (from isopropyl alcohol-methoanol).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([I:13])[C:8]([CH3:12])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[F:14][C:15]([F:24])([F:23])[C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19]>CC(O)C>[I:13][C:7]1[C:8]([CH3:12])=[CH:9][CH:10]=[C:11]2[C:6]=1[CH:5]=[CH:4][N:3]=[C:2]2[NH:19][C:18]1[CH:20]=[CH:21][CH:22]=[C:16]([C:15]([F:14])([F:23])[F:24])[CH:17]=1
Reactant: Cc1ccc2c(Cl)nccc2c1I
Reactant: Nc1cccc(C(F)(F)F)c1
Solvent: CC(C)O
Product: Cc1ccc2c(Nc3cccc(C(F)(F)F)c3)nccc2c1I
Temperature: 140 °C
Reaction time: 0.33 h
Yield: 49.9 %

Procedure:
To a solution of 1-chloro-5-iodo-6-methylisoquinoline (0.400 g, 1.32 mmol) in IPA (5.00 ml), charged to a 5 mL mircowave reaction vessel, 3-(trifluoromethyl)aniline (0.329 ml, 2.64 mmol) was added. The reaction mixture was stirred at 140° C. for 20 min. The resulting ppt was collected by filtration and washed with excess IPA. The solid was dried under vaccum to give 5-iodo-6-methyl-N-(3-(trifluoromethyl)phenyl)isoquinolin-1-amine (0.282 g, 50.0% yield) as a pale solid. MS (M+H)+ 429.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@H:3]([OH:6])[CH2:2]1.[CH2:7]=[C:8]1[O:12][C:10](=[O:11])[CH2:9]1>O1CCCC1>[OH:6][C@H:3]1[CH2:4][CH2:5][N:1]([C:10](=[O:11])[CH2:9][C:8](=[O:12])[CH3:7])[CH2:2]1
Reactant: C=C1CC(=O)O1
Reactant: O[C@H]1CCNC1
Solvent: C1CCOC1
Product: CC(=O)CC(=O)N1CC[C@H](O)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
A solution of 21.8 g (0.25 mol) (S)-3-pyrrolidinol in 200 ml tetrahydrofuran was added dropwise to a solution of 20 g of diketene (0.24 mol) in 200 ml of tetrahydrofuran at −5 to 0° C. added. After 1 h stirring at 0° C. no more starting material was detected by thin layer chromatography. The reaction mixture was evaporated and the residue purified by column chromatography. This gave 31.35 g (0.18 mol, 77% yield) of a colorless oil.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH2:30][C:31](O)=[O:32])[CH:25]=[C:26]([O:28][CH3:29])[CH:27]=1>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:19])[N:2]([NH:1][C:31](=[O:32])[CH2:30][C:24]3[CH:23]=[C:22]([O:21][CH3:20])[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=3)[N:11]=2)=[CH:13][CH:14]=1
Reactant: Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O
Reactant: COc1cc(CC(=O)O)cc(OC)c1
Product: COc1cc(CC(=O)Nn2nc(-c3ccc(Cl)cc3)c3ccccc3c2=O)cc(OC)c1

Procedure:
The product of Example 86A and 2-(3,5-dimethoxyphenyl)acetic acid were treated using a method similar to that described in Example 57 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.41-8.43 (m, 1H), 7.90-8.04 (m, 2H), 7.72-7.74 (m, 1H), 7.62-7.66 (m, 4H), 6.58 (d, J=2.3 Hz, 2H), 6.41 (t, J=2.3 Hz, 1H), 3.75 (s, 6H), 3.74 (s, 2H); MS (ESI−) M/Z 448 (M−H)−.
Reaction SMILES: C(N(CC)CC)C.[S].[C:9]([O:12][C@H:13]1[CH2:17][CH2:16][C@H:15]([CH2:18][OH:19])[C@H:14]1[CH2:20][CH2:21][S:22][C:23]1[S:24][CH:25]=[C:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:27]=1)(=[O:11])[CH3:10].Cl>C(OCC)(=O)C.CS(C)=O>[C:9]([O:12][C@H:13]1[CH2:17][CH2:16][C@H:15]([CH:18]=[O:19])[C@H:14]1[CH2:20][CH2:21][S:22][C:23]1[S:24][CH:25]=[C:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:27]=1)(=[O:11])[CH3:10]
Reactant: CCOC(=O)c1csc(SCC[C@@H]2[C@@H](CO)CC[C@@H]2OC(C)=O)n1
Agent: Cl
Agent: [S]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCOC(=O)c1csc(SCC[C@H]2[C@@H](OC(C)=O)CC[C@@H]2C=O)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.9 %

Procedure:
Triethylamine (3.7 mL) and sulfur trioxidepyridine complex (1.7 g) were added to a dimethyl sulfoxide (4.0 mL)/ethyl acetate (8.0 mL) solution of ethyl 2-({2-[(1R,2S,5S)-2-(acetyloxy)-5-(hydroxymethyl)cyclopentyl]ethyl}thio)-1,3-thiazole-4-carboxylate (500 mg) (see compound 7 described in the pamphlet of International Publication No. WO 2006/129788) at 10° C., followed by stirring at room temperature for 30 min. To the reaction solution, 1 N hydrochloric acid was added, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine; dried with anhydrous sodium sulfate; and concentrated to obtain the title compound (497 mg) having the following physical properties:
Reaction SMILES: C(O)(=O)C.[NH2:5][CH2:6][C@@H:7]([C:16]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]2[C:17]=1[CH:18]=[CH:19][C:20](=[O:27])[NH:21]2)[O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].[CH3:28][O:29][C:30]1[CH:31]=[C:32]([NH:36][C:37]2[C:46]3[C:41](=[C:42]([CH3:68])[CH:43]=[C:44]([S:47]([C:50]4[CH:55]=[CH:54][CH:53]=[C:52]([C:56](=[O:67])[NH:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH:65]=O)[CH:51]=4)(=[O:49])=[O:48])[CH:45]=3)[N:40]=[CH:39][C:38]=2[C:69]([NH2:71])=[O:70])[CH:33]=[CH:34][CH:35]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>CN(C=O)C>[Si:9]([O:8][C@H:7]([C:16]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]2[C:17]=1[CH:18]=[CH:19][C:20](=[O:27])[NH:21]2)[CH2:6][NH:5][CH2:65][CH2:64][CH2:63][CH2:62][CH2:61][CH2:60][CH2:59][CH2:58][NH:57][C:56]([C:52]1[CH:51]=[C:50]([S:47]([C:44]2[CH:45]=[C:46]3[C:41](=[C:42]([CH3:68])[CH:43]=2)[N:40]=[CH:39][C:38]([C:69]([NH2:71])=[O:70])=[C:37]3[NH:36][C:32]2[CH:33]=[CH:34][CH:35]=[C:30]([O:29][CH3:28])[CH:31]=2)(=[O:48])=[O:49])[CH:55]=[CH:54][CH:53]=1)=[O:67])([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CN)c1ccc(O)c2[nH]c(=O)ccc12
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)NCCCCCCCC=O)c4)cc23)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)NCCCCCCCCNC[C@H](O[Si](C)(C)C(C)(C)C)c5ccc(O)c6[nH]c(=O)ccc56)c4)cc23)c1
Reaction time: 3 h
Yield: 91.3 %

Procedure:
Glacial acetic acid (0.005 mL, 0.089 mmol) and Intermediate 2 (50 mg, 0.149 mmol) were added to a stirring solution of Intermediate 112 (55 mg, 0.089 mmol) in DMF (2 mL) at rt. The resulting solution was stirred for 3 h, then NaBH(OAc)3 (57 mg, 0.267 mmol) was added in portions. The reaction mixture was stirred over night then poured into said. NaHCO3 (40 mL). The precipitate was filtered, washed with H2O (50 mL), and dried to give the title compound (76 mg) as a yellow solid. The compound was used with no further purification. ES/MS calcd. for C50H63N6O8SSi+ 935.4. Found m/z=935.4 (M+H+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][N:8]([CH2:30][CH2:31][CH3:32])[CH:9]2[CH2:18][C:17]3[CH:16]=[C:15]([O:19][S:20]([C:23]4[C:24]([CH3:29])=[N:25][O:26][C:27]=4[CH3:28])(=[O:22])=[O:21])[CH:14]=[CH:13][C:12]=3[CH2:11][CH2:10]2)[CH2:3][CH2:2]1.C(OC([N:40]1[CH2:45][CH2:44][CH:43]([C:46](O)=[O:47])[CH2:42][CH2:41]1)=O)(C)(C)C.CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C>ClCCl>[NH:40]1[CH2:45][CH2:44][CH:43]([C:46]([N:1]2[CH2:6][CH2:5][CH:4]([CH2:7][N:8]([CH2:30][CH2:31][CH3:32])[CH:9]3[CH2:18][C:17]4[CH:16]=[C:15]([O:19][S:20]([C:23]5[C:24]([CH3:29])=[N:25][O:26][C:27]=5[CH3:28])(=[O:22])=[O:21])[CH:14]=[CH:13][C:12]=4[CH2:11][CH2:10]3)[CH2:3][CH2:2]2)=[O:47])[CH2:42][CH2:41]1
Reactant: CCCN(CC1CCNCC1)C1CCc2ccc(OS(=O)(=O)c3c(C)noc3C)cc2C1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCN(CC1CCN(C(=O)C2CCNCC2)CC1)C1CCc2ccc(OS(=O)(=O)c3c(C)noc3C)cc2C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 89.7 %

Procedure:
Under an inert atmosphere 3,5-dimethyl-isoxazole-4-sulfonic acid 7-(piperidin-4-ylmethyl-propyl-amino)-5,6,7,8-tetrahydro-naphthalen-2-yl ester (400 mg, 0.87 mmol), piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (199 mg, 0.87 mmol, 1 eq.), EDCl (166 mg, 0.87 mmol, 1 eq.), triethylamine (0.25 mL, 1.79 mmol, 2 eq.), and dichloromethane (35 mL) were combined. The mixture was stirred at room temperature for 48 h and then concentrated in vacuo. The residue was taken up in EtOAc (50 mL) and washed with water (30 mL), 1 N NaOH (30 mL), brine (30 mL), and then dried (MgSO4). The solution was filtered and concentrated to afford a yellow oil. The oil was flash chromatographed on silica gel eluting with 20% acetone in hexanes to afford the protected amine as a foam (447 mg), which was deprotected with trifluoroacetic acid, as described herein, to afford 3,5-dimethyl-isoxazole-4-sulfonic acid 7-{[1-(piperidine-4-carbonyl)-piperidin-4-ylmethyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-yl ester (320 mg), 114M+H]+=609.
Reaction SMILES: [CH:1]1([O:4][CH2:5][CH:6]2[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]2)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([O:4][CH2:5][CH:6]2[CH2:7][CH2:8][NH:9][CH2:10][CH2:11]2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(COC2CC2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C1CC(COC2CC2)CCN1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.2 %

Procedure:
To a solution of 2.0 g of tert-butyl 4-[(cyclopropyloxy)methyl]piperidine-1-carboxylate in 20 mL of dichloromethane was added 3.0 mL of trifluoroacetic acid, followed by stirring at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and to the residue were added a saturated aqueous sodium hydrogen carbonate solution and ethyl acetate, and then the aqueous layer was separated. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (chloroform/methanol) to obtain 756 mg of 4-[(cyclopropyloxy)methyl]piperidine.
Reaction SMILES: Br[C:2]1[C:3]([F:19])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:18]=1.[F:20][C:21]([F:28])([F:27])[C:22]([CH3:26])([OH:25])[C:23]#[CH:24]>>[F:19][C:3]1[C:2]([C:24]#[C:23][C:22]([OH:25])([CH3:26])[C:21]([F:28])([F:27])[F:20])=[CH:18][C:6]2[C:7]3[N:8]([CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=3)[CH2:9][CH2:10][O:11][C:5]=2[CH:4]=1
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)c(F)cc1OCC2
Reactant: C#CC(C)(O)C(F)(F)F
Product: CC(O)(C#Cc1cc2c(cc1F)OCCn1cc(C(N)=O)nc1-2)C(F)(F)F
Yield: 40 %

Procedure:
Similar to as described in General Procedure G, 10-bromo-9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with 1,1,1-trifluoro-2-methylbut-3-yn-2-ol (US2005/250741 A1) to give the titled compound as a white solid (80 mg, 40%).
Reaction SMILES: [C:1]([C:4]1[C:5]([Cl:17])=[C:6]2[C:11](=[C:12]([CH3:14])[CH:13]=1)S[CH2:9][CH2:8][C:7]2([CH3:16])[CH3:15])(=[O:3])[CH3:2].OO.[S:20]([O-:23])(O)=[O:21].[Na+]>C(O)(=O)C>[C:1]([C:4]1[C:5]([Cl:17])=[C:6]2[C:11](=[C:12]([CH3:14])[CH:13]=1)[S:20](=[O:23])(=[O:21])[CH2:9][CH2:8][C:7]2([CH3:16])[CH3:15])(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(C)c2c(c1Cl)C(C)(C)CCS2
Reactant: O=S([O-])O
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)c1cc(C)c2c(c1Cl)C(C)(C)CCS2(=O)=O
Temperature: 80 °C
Yield: 85 %

Procedure:
5 ml of acetic acid was added to 3.0 g (11 mmol) of 6-acetyl-5-chloro-4,4,8-trimethylthiochroman, 3.7 g (33 mmol) of a 30% hydrogen peroxide aqueous solution was further added, and the mixture was heated at 80° C. for 2 hours. 20 ml of a 2% sodium hydrogensulfite was added to the reaction mixture, and a precipitated solid was recovered by filtration to give 2.8 g (yield 85%) of 6-acetyl-5-chloro-4,4,8-trimethylthiochroman-1,1-dioxide.
Reaction SMILES: [CH:1]([C:3]1[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][O:19][CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][O:21]3)=[CH:14][CH:13]=2)=[N:5][C:6]([S:9][CH3:10])=[N:7][CH:8]=1)=O.[Br:26][C:27]1[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=1[NH2:29]>>[Br:26][C:27]1[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=1[NH:29][CH2:1][C:3]1[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][O:19][CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][O:21]3)=[CH:14][CH:13]=2)=[N:5][C:6]([S:9][CH3:10])=[N:7][CH:8]=1
Reactant: Nc1ccccc1Br
Reactant: CSc1ncc(C=O)c(Nc2ccc(COC3CCCCO3)cc2)n1
Product: CSc1ncc(CNc2ccccc2Br)c(Nc2ccc(COC3CCCCO3)cc2)n1
Yield: 24 %

Procedure:
Reaction of 4.0 g (11.1 mmol) of 5-formyl-4-[4-(tetrahydropyran-2-yloxymethyl)phenyl]amino-2-methylthiopyrimidine with 2-bromoaniline in a method analogous to Example 37(f) gave 1.13 g (24%) of 5-(2-bromoanilino)methyl-4-[4-(tetrahydropyran-2-yloxymethyl)phenyl]amino-2-methylthiopyrimidine as a pale yellow gum. [Mass spectrum (ESI) MH+ =515].
Reaction SMILES: [C:1]([N:4]1[CH2:11][S:10][CH2:9][C@@H:5]1[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2].[CH3:12][O:13][C:14](=[O:25])[C@H:15]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1)[NH2:16].C(N1CSC[C@@H]1C(O)=O)(=O)C.COC(=O)[C@H](CC1C=CC(O)=CC=1)N.[H-].[Na+].[Cl:53][C:54]1[N:59]=[C:58](Cl)[CH:57]=[CH:56][N:55]=1>CN(C=O)C.O>[C:1]([N:4]1[CH2:11][S:10][CH2:9][C@@H:5]1[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2].[CH3:12][O:13][C:14](=[O:25])[C@H:15]([CH2:17][C:18]1[CH:19]=[CH:20][C:21]([O:24][C:56]2[CH:57]=[CH:58][N:59]=[C:54]([Cl:53])[N:55]=2)=[CH:22][CH:23]=1)[NH2:16]
Reactant: Clc1ccnc(Cl)n1
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)cc1
Agent: CC(=O)N1CSC[C@@H]1C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)[C@@H](N)Cc1ccc(Oc2ccnc(Cl)n2)cc1
Yield: 65.8 %

Procedure:
A solution of N-acetyl-D-thioproline-L-tyrosine methyl ester (1.76 g, 5 mmol), [prepared from N-acetyl-D-thioproline and tyrosine methyl ester by a similar method to the preparation of Intermediate 5] in DMF (10 ml) was added to a suspension of sodium hydride (60% in mineral oil, 210 mg, 5.25 mmol) in DMF (5 ml) at room temperature. After 10 min a solution of 2,4-dichloropyrimidine (782 mg, 5.25 mmol) in DMF (5 ml) was added. After 1 h water (1 ml) was added and the solvent evaporated in vacuo. The residue was dissolved in EtOAc (200 ml) and washed with water (3×50 ml) and brine (30 ml), dried (Na2SO4) and evaporated in vacuo. Chromatography (SiO2, MeOH/DCM 5:95) gave the title compound as a white foam (1.59 g, 68%). δH (DMSO-d6, 400K) 8.56 (1 H, d, J 5.7 Hz, PyrH), 7.9 (1 H, br d, CONH),7.32 (2 H, d,J 8.7 Hz, ArH), 7.15 (2 H, d, J 8.7 Hz, ArH), 6.99 (1 H, d, J 5.7 Hz, PyrH), 4.83 (1 H, dd, J 7.4, 3.9 Hz, CHαthiopro), 4.77 (1 H, d, J 9.2 Hz, NCHHBS), 4.64 (1 H,dt, J 8.5, 5.6 Hz, CHαtyr),4.39 (1 H, d, J 9.2 Hz, NCHAHBS), 3.67 (3 H, s, CO2Me), 3.26 (1 H, dd, J 11.6, 7.4 Hz, CHCHAHBS), 3.19 (1 H, dd, J 14.0, 5.7 Hz, CHCHAHBAr), 3.09-3.00 (2 H, m, CHCHAHBS+CHCHAHBAr) and 2.00 (3 H, s,COCH3); m/z (ESI, 15 V) 465 (MH+).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]4[C:28]([O:30]CC)=[O:29])=[O:21])=[CH:14][C:13]=3[C:33]([F:36])([F:35])[F:34])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[OH-].[Na+].CCO>>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]4[C:28]([OH:30])=[O:29])=[O:21])=[CH:14][C:13]=3[C:33]([F:35])([F:34])[F:36])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C1CCCCN1C(=O)/C=C/c1ccc(Sc2ccc3c(c2)OCCO3)c(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C1CCCCN1C(=O)/C=C/c1ccc(Sc2ccc3c(c2)OCCO3)c(C(F)(F)F)c1

Procedure:
The title compound was prepared by hydrolysis of the compound of Example 249 under basic conditions (aq. NaOH/EtOH), resulting in a white solid, mp 90° C. (dec.). 1H NMR (DMSO-d6, 300 MHz) δ 1.15-1.50 (m, 2H), 1.50-1.70 (m, 2H), 2.16 (m, 1H), 2.56 (m, 1H), 3.15 (m, 1H), 4.30 (s, 4H), 4.32 (m, 1H), 5.20 (m, 1H), 7.02 (m, 4H), 7.30-7.52 (m, 2H), 7.84 (m, 1H), 8.15 (s, 1H). MS (APCI) m/z 494 (M+H)+. Anal. calcd. for C24H22F3NO5.0.3H2O: C, 57.78; H, 4.57; N, 2.81. Found: C, 57.87; H, 4.5 7; N, 2.76.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=3)[C:18](Cl)=[O:19])[N:11]=2)[CH:7]=[CH:6][C:5]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH3:30].Cl.[CH3:32][O:33][C:34](=[O:37])[CH2:35][NH2:36]>>[CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=3)[C:18]([NH:36][CH2:35][C:34]([O:33][CH3:32])=[O:37])=[O:19])[N:11]=2)[CH:7]=[CH:6][C:5]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH3:30]
Reactant: COCc1cc(-c2nc(-c3cccc(C(=O)Cl)c3)no2)ccc1-c1ccccc1C
Reactant: COC(=O)CN
Agent: Cl
Product: COCc1cc(-c2nc(-c3cccc(C(=O)NCC(=O)OC)c3)no2)ccc1-c1ccccc1C

Procedure:
3-{5-[2-(methoxymethyl)-2′-methylbiphenyl-4-yl]-1,2,4-oxadiazol-3-yl}benzoyl chloride was prepared following procedure described in example 116 starting from example 92. It was obtained as an oil (1070 mg, 96%). The title compound was prepared following procedure described in example 121 starting from 3-{5-[2-(methoxymethyl)-2′-methylbiphenyl-4-yl]-1,2,4-oxadiazol-3-yl}benzoyl chloride and glycine methyl ester hydrochloride. The title compound was obtained as a pale yellow powder (97 mg, 86%). 1H NMR: (DMSO-d6, 300 MHz) δ 9.27 (m, 1H), 8.63 (m, 1H), 8.35 (m, 1H), 8.31 (m, 1H), 8.19 (dd, J=1.8 Hz, 7.9 Hz, 1H), 8.12 (m, 1H), 7.76 (t, J=7.9 Hz, 1H), 7.43 (d, J=7.9 Hz, 1H), 7.39-7.26 (m, 3H), 7.15 (m, 1H), 4.23 (d, J=12.9 Hz, 1H), 4.17 (d, J=12.9 Hz, 1H), 4.07 (d, J=5.8 Hz, 1H), 3.68 (s, 3H), 3.25 (s, 3H), 2.04 (s, 3H). LC/MS (Method B): 472.2 (M+H)+ 470.2 (M−H)−. HPLC (Method A) Rt: 4.92 min (purity: 99.2%).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([CH2:8][CH2:9][S:10]([CH3:13])(=[O:12])=[O:11])=[CH:6][C:5]([C:14]([NH2:16])=O)=[N:4]1)[CH3:2].[OH-].[NH4+]>P(Cl)(Cl)(Cl)=O>[CH2:1]([N:3]1[C:7]([CH2:8][CH2:9][S:10]([CH3:13])(=[O:12])=[O:11])=[CH:6][C:5]([C:14]#[N:16])=[N:4]1)[CH3:2]
Reactant: CCn1nc(C(N)=O)cc1CCS(C)(=O)=O
Agent: [NH4+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: CCn1nc(C#N)cc1CCS(C)(=O)=O
Reaction time: 0.5 h
Yield: 96.7 %

Procedure:
A modification of the method described in Part E of Examples 1-4 was used to treat 1-ethyl-5-(2-methanesulfonylethyl)-1H-pyrazole-3-carboxamide (3.46 g, 14.1 mmol) with phosphorous oxychloride (10 mL). The reaction was heated for 2.5 hours. After the addition of ammonium hydroxide (35 mL of 28%) a precipitate formed. The mixture was stirred for 30 minutes, and the precipitate was isolated by filtration and washed with water to provide 3.1 g of 1-ethyl-5-(2-methanesulfonylethyl)-1H-pyrazole-3-carbonitrile as a white powder.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([N:10]([C:17]2[N:21]([CH3:22])[C:20]3[CH:23]=[CH:24][C:25]([N:27]([C:29]4[CH:34]=[CH:33][N:32]=[C:31](Cl)[N:30]=4)[CH3:28])=[CH:26][C:19]=3[N:18]=2)C(=O)C(C)(C)C)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:36][S:37]([CH2:40][C:41]1[CH:42]=[C:43]([CH:45]=[CH:46][CH:47]=1)[NH2:44])(=[O:39])=[O:38]>>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:17]2[N:21]([CH3:22])[C:20]3[CH:23]=[CH:24][C:25]([N:27]([C:29]4[CH:34]=[CH:33][N:32]=[C:31]([NH:44][C:43]5[CH:45]=[CH:46][CH:47]=[C:41]([CH2:40][S:37]([CH3:36])(=[O:39])=[O:38])[CH:42]=5)[N:30]=4)[CH3:28])=[CH:26][C:19]=3[N:18]=2)[CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CN(c1ccc2c(c1)nc(N(C(=O)C(C)(C)C)c1cc(C(C)(C)C)on1)n2C)c1ccnc(Cl)n1
Reactant: CS(=O)(=O)Cc1cccc(N)c1
Product: CN(c1ccc2c(c1)nc(Nc1cc(C(C)(C)C)on1)n2C)c1ccnc(Nc2cccc(CS(C)(=O)=O)c2)n1

Procedure:
The title compound was prepared following the procedure of Example 134 with N-(5-tert-Butyl-isoxazol-3-yl)-N-{5-[(2-chloro-pyrimidin-4-yl)-methyl-amino]-1-methyl-1H benzoimidazole-2-yl}-2,2-dimethyl-propionamide (23 mg, 0.045 mmol) and 3-[(methylsulfonyl)methyl]aniline (10 mg, 0.139 mmol) to afford a white solid (5 mg, 0.01 mmol). MS (ESI) m/z=561 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](Cl)=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([C:32]2([C:35]([NH:37][C:38]3[CH:43]=[CH:42][C:41]([OH:44])=[C:40]([F:45])[CH:39]=3)=[O:36])[CH2:34][CH2:33]2)=[O:31])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[F:22][C:23]1[CH:24]=[CH:25][C:26]([NH:29][C:30]([C:32]2([C:35]([NH:37][C:38]3[CH:43]=[CH:42][C:41]([O:44][C:13]4[C:12]5[C:17](=[CH:18][C:9]([O:8][CH2:1][C:2]6[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=6)=[C:10]([O:20][CH3:21])[CH:11]=5)[N:16]=[CH:15][N:14]=4)=[C:40]([F:45])[CH:39]=3)=[O:36])[CH2:34][CH2:33]2)=[O:31])=[CH:27][CH:28]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCc1ccccc1
Reactant: O=C(Nc1ccc(F)cc1)C1(C(=O)Nc2ccc(O)c(F)c2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1cc2c(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)ncnc2cc1OCc1ccccc1
Temperature: 50 °C
Reaction time: 16 h
Yield: 75.4 %

Procedure:
A mixture of 7-benzyloxy-4-chloro-6-methoxy-quinazoline (5 g, 16.67 mmol), cyclopropane-1,1-dicarboxylic acid (3-fluoro-4-hydroxy-phenyl)-amide (4-fluoro-phenyl)-amide (8.3 g, 25 mmol), potassium carbonate (125 mmol, 17.25 g), and dimethylacetamide (125 ml) was heated 50° C. with stirring for 16 h. Reaction mixture was poured onto ice/water (600 ml) and stirred for 30 minutes, and filtered. The solid was dissolved in ethyl acetate and washed with water (1×), brine, and concentrated. The crude was purified on silica get column eluting with 30% acetone in hexanes to yield cyclopropane-1,1-dicarboxylic acid [4-(7-benzyloxy-6-methoxy-quinazolin-4-yloxy)-3-fluoro-phenyl]-amide (4-fluoro-phenyl)-amide (7.5 g, 76%). 1H NMR (CDCl3): 8.64 (1H, br. s), 8.55 (1H, s), 8.33 (1H, br. s), 7.74-7.71 (1H, dd), 7.54 (1H, s), 7.48-7.33 (8H, m), 7.31-7.24 (2H, m), 7.06-7.02 (2H, m), 5.32 (2H, s), 4.06 (3H, s), 1.77-1.74 (2H, m), 1.63-1.61 (2H, m).