Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].Cl[C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[CH:5][N:4]=1.Br[C:25]1[C:31]([OH:32])=[CH:30][C:28]([NH2:29])=[C:27]([F:33])[CH:26]=1>C(O)(C)C.CC(C)=O>[Cl:1][C:25]1[C:31]([OH:32])=[CH:30][C:28]([NH:29][C:3]2[C:12]3[C:7](=[CH:8][C:9]([O:15][CH2:16][CH2:17][N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[C:10]([O:13][CH3:14])[CH:11]=3)[N:6]=[CH:5][N:4]=2)=[C:27]([F:33])[CH:26]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCN1CCOCC1
Reactant: Cl
Reactant: Nc1cc(O)c(Br)cc1F
Solvent: CC(C)O
Solvent: CC(C)=O
Product: COc1cc2c(Nc3cc(O)c(Cl)cc3F)ncnc2cc1OCCN1CCOCC1
Yield: 20.6 %

Procedure:
1M Ethereal hydrogen chloride (0.72 ml, 0.72 mmol) was added to 4-chloro-6-methoxy-7-(2-morpholinoethoxy)quinazoline (210 mg, 0.65 mmol) and 4-chloro-2-fluoro-5-hydroxyaniline (115 mg, 0.71 mmol), (as described in EP 61741 A2), in isopropanol (5 ml) and the mixture heated at reflux for 2 hours and then allowed to cool. The mixture was diluted with acetone and the precipitated product collected by filtration. The impure product was dissolved in methylene chloride/ammonia (100/1) and methanol, the insolubles removed by filtration and the volatiles were removed from the filtrate by evaporation. The solid residue was washed with water and dried to give 4-(4-chloro-2-fluoro-5-hydroxyanilino)-6-methoxy-7-(2-morpholinoethoxy)quinazoline (60 mg, 21%).
Reaction SMILES: S(=O)(=O)(O)O.CO.[NH2:8][C:9]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:15]([O:24][CH3:25])=[CH:14][C:10]=1[C:11]([OH:13])=[O:12].[C:26](=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[NH2:8][C:9]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:15]([O:24][CH3:25])=[CH:14][C:10]=1[C:11]([O:13][CH3:26])=[O:12]
Reactant: O=C([O-])O
Reactant: COc1cc(C(=O)O)c(N)cc1-c1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(OC)c(-c2ccccc2)cc1N
Temperature: 25 °C

Procedure:
Under ice-cooling, concentrated sulfuric acid (1 mL) was added to a methanol (10 mL) suspension of the obtained 2-amino-5-methoxy-4-phenylbenzoic acid, followed by heating to reflux for 6 hours. The reaction mixture was cooled to room temperature and adjusted to a pH of 8.0 with a saturated aqueous solution of sodium bicarbonate, and then chloroform was added thereto. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Hexane was added to the obtained residue, and the solid substance was collected by filtration to obtain 0.24 g of methyl 2-amino-5-methoxy-4-phenylbenzoate as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].[NH2:30][CH2:31][C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][NH:30][CH2:31][C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Reactant: NCc1cccnc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(CNCc3cccnc3)ccc21

Procedure:
In a similar manner to Step 1 of Example 56, 4-chloro-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (20.0 mg, 0.0487 mmol) was dissolved in dichloromethane (0.5 mL). The solution was treated with 3-aminomethylpyridine (0.010 mL, 0.098 mmol) and sodium triacetoxyborohydride (32 mg, 0.15 mmol) to obtain 4-chloro-7-(1-(tert-butoxycarbonyl)-5-[(pyridin-3-ylmethyl)amino methyl]indol-2-yl)isoindolinone.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:21]N1C(=O)CCC1=O>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[Br:21][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:8][CH2:9][O:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: c1ccc(CCCOc2cccc3ccccc23)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrC(CCOc1cccc2ccccc12)c1ccccc1
Temperature: 80 °C
Yield: 100.4 %

Procedure:
A mixture of 26.2 g (0.1 mol) of 1-phenyl-3-(1-naphthalenyloxy)propane, 17.8 g (0.1 mol) of N-bromosuccinimide, 120 ml of carbon tetrachloride and 250 mg of benzoyl peroxide was heated at 80° C. for four hours. The mixture was cooled and the precipitated solid was collected by vacuum filtration. The mother liquor was concentrated under vacuum to provide 34.26 g of a red oil.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].[CH:11]1[C:20]2[C:15](=[C:16]([CH:21]([CH3:25])[C:22](O)=[O:23])[CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][N:12]=1.C1C2C(=C(CC(O)=O)C=CC=2)C=CN=1>>[Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH2:4][NH:5][C:22](=[O:23])[CH:21]([C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:15]=1[CH:14]=[CH:13][N:12]=[CH:11]2)[CH3:25]
Reactant: NCc1ccc(Cl)cc1Cl
Reactant: CC(C(=O)O)c1cccc2cnccc12
Agent: O=C(O)Cc1cccc2cnccc12
Product: CC(C(=O)NCc1ccc(Cl)cc1Cl)c1cccc2cnccc12

Procedure:
The title compound was prepared using the procedure described in Example 222B using 2,4-dichlorobenzylamine and 2-(5-isoquinolinyl)propanoic acid instead of 4-(trifluoromethoxy)benzylamine and 5-isoquinolinylacetic acid. MS (ESI+) m/z 359 (M+H)+; MS (ESI−) m/z 357 (M−H)−; 1H NMR (DMSO, 300 MHz) δ 1.54 (d, J 7.1, 3H), 4.20 (m, 2H), 4.53 (q, J 7.1, 1H), 7.22 (d, J 8.4, 1H), 7.33 (m, 2H), 7.56 (s, 1H), 7.78 (t, J 7.8, 1H), 7.90 (d, J 6.5, 1H), 8.17 (d, J 8.1, 1H), 8.25 (d, J 6.4, 1H), 8.62 (m, 2H), 9.51 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8](Br)=[CH:7][C:5]=2[N:6]=1.CN(C)CCN(C)C.C([Li])(C)(C)C.[B:25](OC(C)C)([O:30]C(C)C)[O:26]C(C)C.S(=O)(=O)(O)O>C1COCC1.CCCCC>[NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([B:25]([OH:30])[OH:26])=[CH:7][C:5]=2[N:6]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Nc1nc2cc(Br)ccc2s1
Agent: CN(C)CCN(C)C
Agent: O=S(=O)(O)O
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: Nc1nc2cc(B(O)O)ccc2s1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of Intermediate 75 (459.1 mg) in anhydrous THF (30 ml) was added with N,N,N′,N′-tetramethylethylenediamine (1.51 ml, WAKO), cooled to −78° C. under argon gas atmosphere, then added dropwise with a 1.62 M solution of t-butyllithium in pentane (7.06 ml), and stirred for 30 minutes. The reaction mixture was added dropwise with (iPrO)3B (2.77 ml), stirred for 30 minutes, then warmed to room temperature, and further stirred for 1.5 hours. The reaction mixture was added with 0.5 M aqueous sulfuric acid (7.5 ml) and extracted with diethyl ether (50 ml×3). The organic layer was washed with saturated brine and dried, and then the solvent was evaporated under reduced pressure to obtain crude 2-amino-5-benzothiazoleboronic acid. This compound was reacted with Compound No. A-1 (344 mg), 2 M aqueous sodium carbonate (4.5 ml) and (Ph3P)4Pd (179 mg) and treated according to the procedure described in the synthesis method of Compound No. V-3 with the modifications that the reaction was carried out for 12 hours, and the purification was performed by flash column chromatography (hexane:ethyl acetate=2:1) to obtain the title compound (Compound No. V-77, 76 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:16](Cl)(=[O:18])[CH3:17]>ClCCl>[C:16]([O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)Cl
Reactant: Oc1cccc(Br)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Oc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.4 %

Procedure:
3-Bromophenol (100 g, 580 mmol) and triethylamine (104 mL, 750 mmol) were dissolved in dichloromethane (500 mL), and the solution was cooled in an ice bath. Acetyl chloride (49.7 g, 630 mmol) was added dropwise. After 1 h the cooling bath was removed and the mixture was stirred overnight (approx 16 h) at room temperature. The mixture was washed with hydrochloric acid (1N, 250 mL), water (250 mL), 5% NaHCO3 (250 mL), and brine (250 mL). The organic layer was dried and evaporated to provide 124 g (99%) of 3-bromophenyl acetate as a light brown liquid; 1H NMR (CDCl3) δ 7.36 (d, 1H), 7.32-7.20 (m, 2H), 7.05 (d, 1H), 2.28 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]([OH:17])=[O:16])=[C:13]([CH3:18])[N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[C:11](=[O:29])[N:10]2[S:30]([CH3:33])(=[O:32])=[O:31])=[C:5]([S:34]([CH3:37])(=[O:36])=[O:35])[CH:4]=1)#[N:2].Br[CH2:39][CH2:40][OH:41].C(N(CC)CC)C>CN(C=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]([O:17][CH2:39][CH2:40][OH:41])=[O:16])=[C:13]([CH3:18])[N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:27])([F:28])[F:26])[CH:20]=3)[C:11](=[O:29])[N:10]2[S:30]([CH3:33])(=[O:31])=[O:32])=[C:5]([S:34]([CH3:37])(=[O:35])=[O:36])[CH:4]=1)#[N:2]
Reactant: CC1=C(C(=O)O)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(S(C)(=O)=O)C(=O)N1c1cccc(C(F)(F)F)c1
Reactant: OCCBr
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1=C(C(=O)OCCO)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(S(C)(=O)=O)C(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
The reaction was carried out under argon. (4S)-4-[4-Cyano-2-(methylsulfonyl)phenyl]-6-methyl-3-(methylsulfonyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (84 mg, 150 μmol) was initially charged in dry DMF (2 ml), 2-bromoethanol (75 mg, 600 μmol; 4 eq.) and triethylamine (31 mg, 300 μmol; 2 eq.) were added and the mixture was stirred at 70° C. for 8 h. The reaction mixture was then concentrated under reduced pressure, and the residue was taken up in ethyl acetate (50 ml). The organic phase was washed with saturated sodium bicarbonate solution (2×20 ml) and saturated sodium chloride solution (20 ml), dried over solid sodium sulfate, filtered and concentrated under reduced pressure. The crude product was subjected to flash chromatography on silica gel (mobile phase: cyclohexane→cyclohexane/ethyl acetate 1:3). The title compound was obtained as a colorless solid (56 mg, 62% of theory).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]3([C:21]([NH:23][C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)=[O:22])[CH2:20][CH2:19]3)=[O:17])=[C:11]([F:31])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.Cl[C:40](OC1C=CC=CC=1)=[O:41].FC(F)(F)C(O)=O.[OH:56][CH2:57][CH:58]1[CH2:61][NH:60][CH2:59]1>O1CCCC1>[F:31][C:11]1[CH:10]=[C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:40]([N:60]3[CH2:61][CH:58]([CH2:57][OH:56])[CH2:59]3)=[O:41])[CH:7]=2)[CH:14]=[CH:13][C:12]=1[NH:15][C:16]([C:18]1([C:21]([NH:23][C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)=[O:22])[CH2:20][CH2:19]1)=[O:17]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: OCC1CNC1
Reactant: Nc1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)c(F)c2)ccn1
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)c(F)c2)ccn1)N1CC(CO)C1
Reaction time: 1 h
Yield: 23.1 %

Procedure:
N-{4-[(2-Aminopyridin-4-yl)oxy]-2-fluorophenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (75 mg) was dissolved in tetrahydrofuran (1.8 ml) under a nitrogen atmosphere, and triethylamine (0.074 ml) and phenyl chloroformate (0.0488 ml) were added dropwise in this order at room temperature, followed by stirring for 1 hr. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with a 1N aqueous solution of sodium hydroxide, water and brine in this order, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformamide (1.8 ml). This solution was added to a mixture of a crude product of 3-(hydroxymethyl)azetidine trifluoroacetate (209.8 mg, corresponds to 0.671 mmol) and triethylamine (0.658 ml), followed by stirring at room temperature for 12 hr. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with a 1N aqueous solution of sodium hydroxide, water and brine in this order, and dried over anhydrous sodium sulfate. The solvent was removed and the residue was purified by silica gel column chromatography (eluent; ethyl acetate, ethyl acetate:methanol=50:1, 20:1, then 10:1). Fractions containing the target compound were concentrated. To the resultant residue (36.9 mg) was added diethyl ether:heptane=1:2 to suspend a solid. The solid was collected by filtration and washed with heptane. This was dried under aeration to provide the titled compound as white powder (22.0 mg, 23.1%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:60])[C@@H:4]([CH3:59])[NH:5][C:6](=[O:58])[C@H:7]([CH2:49][O:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[NH:8][C:9](=[O:48])[C@@H:10]([CH2:33][C:34]1[CH:39]=[CH:38][C:37]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[CH:36][CH:35]=1)[NH:11][C:12](=[O:32])[C@H:13]([CH2:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:25][CH:24]=1)[NH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:16].[CH2:61](OC(N[C@H](C(O)=O)CC1C2C(=CC=CC=2)NC=1)=O)[C:62]1C=CC=C[CH:63]=1.C1(N=C=NC2CCCCC2)CCCCC1.C(ON[C@H](C(N[C@@H](C(N[C@H](C(N[C@@H](C(O)=O)C)=O)COCC1C=CC=CC=1)=O)CC1C=CC(OCC2C=CC=CC=2)=CC=1)=O)C(=C=O)C1C2C(=CC=CC=2)NC=1)C1C=CC=CC=1>CN(C)C=O.CO.C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:60])[C@@H:4]([CH3:59])[NH:5][C:6](=[O:58])[C@H:7]([CH2:49][O:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[NH:8][C:9](=[O:48])[C@@H:10]([CH2:33][C:34]1[CH:35]=[CH:36][C:37]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[CH:38][CH:39]=1)[NH:11][C:12](=[O:32])[C@H:13]([CH2:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:25][CH:24]=1)[NH:14][C:15]([O:17][CH2:18][C:19]1[CH:63]=[CH:62][CH:61]=[CH:21][CH:20]=1)=[O:16]
Reactant: O=C(N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O)OCc1ccccc1
Reactant: CCCCOC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)N[C@@H](COCc1ccccc1)C(=O)N[C@H](C)C(=O)OC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: C[C@@H](NC(=O)[C@H](COCc1ccccc1)NC(=O)[C@@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)[C@@H](NOCc1ccccc1)C(=C=O)c1c[nH]c2ccccc12)C(=O)O
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](C)NC(=O)[C@H](COCc1ccccc1)NC(=O)[C@@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OCc1ccccc1

Procedure:
Nα-t-Butoxycarbonyl-O-benzyl-O-tyrosyl-O-benzyl-L-seryl-D-alanine resin (Example 11), 6.4 g., 5.1 mmol, is coupled with 2.23 g., 6.3 mmol, of Nα-benzyloxycarbonyl-L-tryptophan and 1.3 g., 6.3 mmol, of dicyclohexylcarbodiimide according to the general procedure of Example 1. The resulting Nα-benzyloxy-carbonyl-L-tryptophyl-O-benzyl-D-tyrosyl-O-benzyl-L-seryl-D-alanine resin is mixed with 20 ml. of triethylamine, 150 ml. of methanol and 50 ml. of dimethylformamide and let stand overnight. After filtration and evaporation, the crude product is triturated with either-petroleum ether and crystallized from isopropanol; 1.75 g.; [α]D 23 -5° (c. 1.01, DMF).
Reaction SMILES: [CH:1]([C:3]1[N:7]([CH:8]([CH3:10])[CH3:9])[N:6]=[C:5]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:4]=1)=O.[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:9][CH:8]([N:7]1[C:3]([CH2:1][N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[CH:4][C:5]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[N:6]1)[CH3:10]
Reactant: C1COCCN1
Reactant: CC(C)n1nc(C(=O)OC(C)(C)C)cc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)n1nc(C(=O)OC(C)(C)C)cc1CN1CCOCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1,1-Dimethylethyl 5-formyl-1-(1-methylethyl)-1H-pyrazole-3-carboxylate (118 mg) was dissolved in anhydrous DCM (10 ml), morpholine (0.048 ml) was added and the mixture was stirred under nitrogen for 2 h at RT. Sodium triacetoxyborohydride (210 mg) was added and the mixture was stirred at RT for 18 h. Sodium bicarbonate solution (20 ml) and DCM (20 ml) were added and separated then the aqueous layer was re-extracted with DCM (2×20 ml) and separated by hydrophobic frit. The combined organic layers were concentrated in vacuo and the residue was purified by flash chromatography on silica gel (20 g silica) eluting with a gradient of 0-100% ethyl acetate in cyclohexane over 20 mins to give the title compound (101 mg) as a white solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][CH2:8][NH:9][C:10]1[S:11][C:12]([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])=[O:16])=[CH:13][N:14]=1.Cl.[S:25]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26]1.CCN(CC)CC>C(Cl)Cl.CO>[S:25]1[CH:29]=[CH:28][C:27]([S:30]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]2[CH2:7][CH2:8][NH:9][C:10]2[S:11][C:12]([C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH3:23])=[O:16])=[CH:13][N:14]=2)(=[O:32])=[O:31])=[CH:26]1
Reactant: Cc1ccccc1C(=O)c1cnc(NCCC2CCCCN2)s1
Reactant: O=S(=O)(Cl)c1ccsc1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccccc1C(=O)c1cnc(NCCC2CCCCN2S(=O)(=O)c2ccsc2)s1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A mixture of 35.2 mg (0.1 mmol) [2-(2-Piperidin-2-yl-ethylamino)-thiazol-5-yl]-o-tolyl-methanone; hydrochloride, 21.9 mg (0.12 mmol) thiophene-3-sulfonyl chloride (commercially available) and 44.6 ul (0.32 mmol) NEt3 in a mixture of DCM/MeOH 3/1 was stirred at 60° C. for 16 h. After cooling to room temperature the mixture was concentrated and MeOH (1 ml) and formic acid (0.5 ml) was added and the mixture was subjected to reversed phase HPLC purification eluting with a gradient of acetonitrile/water. After evaporation of the product fractions 7 mg (15%) of the title compound was obtained. MS (m/e): 474.0 (MH−, 100%)
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6](=O)[CH2:7][CH2:8][C:2]1=2.[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N:17]=[C:18]=S)[CH:12]=1.C[Si](C)(C)[Si](C)(C)C.[Li].O.[NH2:30][NH2:31]>C1COCC1.O.C(O)(=O)C>[Cl:10][C:11]1[CH:12]=[C:13]([NH:17][C:18]2[C:7]3[CH2:8][C:2]4[S:1][CH:5]=[CH:4][C:3]=4[C:6]=3[NH:31][N:30]=2)[CH:14]=[CH:15][CH:16]=1
Reactant: S=C=Nc1cccc(Cl)c1
Reactant: O=C1CCc2sccc21
Reactant: NN
Agent: C[Si](C)(C)[Si](C)(C)C
Agent: [Li]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: Clc1cccc(Nc2n[nH]c3c2Cc2sccc2-3)c1
Reaction time: 8 h
Yield: 30 %

Procedure:
A mixture of 5,6-Dihydro-cyclopenta[b]thiophen-4-one (1.0 g, 7.4 mmol) and 1-Chloro-3-isothiocyanato-benzene (1.5 g, 7.2 mmol) in THF (2.0 mL) was added to lithium hexamethyl disilane (7.0 mL, 7.2 mmol) dropwise at room temperature. The reaction mixture was stirred for 8 hr. Hydrazine monohydrate (0.4 mL, 7.9 mmol) and glacial acetic acid (0.5 mL) were added to the reaction mixture, which was then heated at the reflux temperature for 24 hr. The resulting mixture was added to water (30 mL) and then extracted with ethyl acetate. The target product was purified by gravity column chromatography (50% EtOAc in hexane) to give (3-Chloro-phenyl)-(4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-6-yl)-amine as brown solid in 30% yield.
Reaction SMILES: [Cl:1][C:2]1[C:16]([Cl:17])=[CH:15][C:5]2[NH:6][C:7]([C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.[CH2:18](Br)[CH:19]=[CH2:20].[In].Cl>C1COCC1>[Cl:17][C:16]1[C:2]([Cl:1])=[CH:3][C:4]2[NH:8][C:7]([C:9]([OH:14])([CH2:20][CH:19]=[CH2:18])[C:10]([F:13])([F:11])[F:12])=[N:6][C:5]=2[CH:15]=1
Reactant: O=C(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F
Reactant: C=CCBr
Agent: Cl
Agent: [In]
Solvent: C1CCOC1
Product: C=CCC(O)(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F

Procedure:
1-(5,6-Dichloro-1H-benzoimidazol-2-yl)-2,2,2-trifluoro-ethanone (1.41 g; 4.99 mmol), allyl bromide (0.85 mL; 10.05 mmol) and indium (1.15 g; 10.05 mmol) were suspended in THF (50 mL) and 0.01 M HCl (150 mL) and stirred vigorously over 18 hours. The layers were separated and the aqueous layer was extracted with ethyl acetate (3×30 mL). The combined extracts were washed with brine (50 mL) and dried over Na2SO4. The resulting crude brown oil was purified by column chromatography (SiO2; 20% ethyl acetate/hexanes) to yield the title compound as a tan solid.
Reaction SMILES: [CH3:1][C:2]([NH:10][C:11]([C:13]1[CH:18]=[N:17][C:16](Br)=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=2)[N:14]=1)=[O:12])([C:4]1[N:8]=[C:7]([CH3:9])[O:6][N:5]=1)[CH3:3].[NH:27]1[CH2:30][CH2:29][CH2:28]1>>[CH3:1][C:2]([NH:10][C:11]([C:13]1[CH:18]=[N:17][C:16]([N:27]2[CH2:30][CH2:29][CH2:28]2)=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=2)[N:14]=1)=[O:12])([C:4]1[N:8]=[C:7]([CH3:9])[O:6][N:5]=1)[CH3:3]
Reactant: Cc1nc(C(C)(C)NC(=O)c2cnc(Br)c(-c3cccc(Cl)c3)n2)no1
Reactant: C1CNC1
Product: Cc1nc(C(C)(C)NC(=O)c2cnc(N3CCC3)c(-c3cccc(Cl)c3)n2)no1

Procedure:
The title compound was synthesized in analogy to Example 4, using 5-bromo-6-(3-chloro-phenyl)-pyrazine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide (Example 1e) and azetidine as starting materials, and isolated (29 mg, 41%) as light yellow oil; MS (EI): 413.2 (M+H).
Reaction SMILES: [NH:1]([C:16]([O:18][C:19]([CH3:22])(C)C)=[O:17])[C@@H:2]([C:13]([OH:15])=[O:14])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([Cl:12])[CH:5]=1.Cl.[CH:24]1[C:36]2C(COC(ON3C(=O)CCC3=O)=O)[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28]=2[CH:27]=[CH:26][CH:25]=1.CCOC(C)=O>O1CCOCC1.O>[NH:1]([C:16]([O:18][CH2:19][CH:22]1[C:27]2[C:28](=[CH:36][CH:24]=[CH:25][CH:26]=2)[C:29]2[C:34]1=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:17])[C@@H:2]([C:13]([OH:15])=[O:14])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([Cl:12])[CH:5]=1
Reactant: COc1ccc(C[C@@H](NC(=O)OC(C)(C)C)C(=O)O)cc1Cl
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(C[C@@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1Cl
Temperature: 23 °C
Reaction time: 18 h

Procedure:
Boc-3-Cl-D-Tyr(Me)-OH (9.60 g, 29.1 mmol) was treated with 4 M HCl in dioxane (25 mL) at 23° C. for 1 h then the reaction mixture was concentrated in vacuo. The residual white solid was dissolved in 10% aqueous Na2CO3 (60 mL), dioxane (60 mL) and N-(9-Fluorenylmethoxy-carbonyloxy)succinimide (9.82 g, 29.1 mmol) were added. The reaction mixture was stirred at 23° C. for 18 h, then diluted with water (100 mL). The aqueous phase was extracted with Et2O (2×100 mL), acidified to pH 2 (conc. HCl) and extracted with EtOAc (3×100 mL). The combined EtOAc phases were washed with saturated aqueous NaCl, dried with MgSO4, filtered and concentrated. Without further purification the title compound 8 (12.65 g, 96%) was obtained as white foam. TLC Rf=0.26 (EtOAc, PMA stain); 1H NMR (CDCl3, 400 MHz) δ 9.82 (br s, 1H), 7.76 (d, J=7.6, 2H), 7.56 (t, J=7.6, 2H), 7.39 (t, J=7.6, 2H), 7.31 (d, J=7.6, 2H), 7.19 (d, J=1.6, 1H), 6.99 (dd, J=8.3, 1.6, 1H), 6.80 (d, J=8.3, 1H), 5.44 (d, J=7.8, 1H), 4.64-4.69 (m, 1H), 4.46 (dd, J=10.5, 7.0, 1H), 4.35 (dd, J=10.5, 7.0, 1H), 4.21 (t, J=7.0, 1H), 3.83 (s, 3H), 3.14 (dd, J=14.1, 5.3, 1H), 3.02 (dd, J=14.1, 6.3, 1H); 13C NMR (CDCl3, 101 MHz) δ 175.0, 155.9, 154.2, 143.7, 141.4, 131.1, 128.8, 128.8, 127.8, 127.2, 125.2, 125.1, 120.1, 112.2, 67.2, 56.1, 54.6, 47.2, 36.8; MS (ESI+) m/z 474.1 [M+Na]+ (C25H22ClNNaO5 requires 474.1).