Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]2[CH:13]=[CH:12][S:11][C:10]=12)=O)C.[BH4-].[Li+].CO.Cl>O1CCCC1>[OH:3][CH2:4][C:6]1[N:7]=[CH:8][N:9]2[CH:13]=[CH:12][S:11][C:10]=12
Reactant: CCOC(=O)c1ncn2ccsc12
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: OCc1ncn2ccsc12
Temperature: 80 °C
Reaction time: 1 h
Yield: 39.7 %

Procedure:
To a solution of 95 mg (0.49 mmol) of the above-obtained 7-ethoxycarbonylimidazo[5,1-b]thiazole in 10 ml of tetrahydrofuran (THF) was added 300 mg of lithium borohydride. The mixture was stirred at 80° C. (the oil bath temperature) for one hour, and then cooled. To this reaction solution, 15 ml of methanol was added little by little with ice-cooling, and the mixture was stirred at room temperature for 30 minutes. Concentrated hydrochloric acid was added to this solution little by little with ice-cooling. The resulting mixture was stirred at room temperature for one hour, and concentrated under reduced pressure. To the residue was added a 50% aqueous solution of potassium carbonate to obtain a solution, which was then extracted four times with methylene chloride. The organic layer was dried over anhydrous potassium carbonate, concentrated under reduced pressure, and purified by flash column chromatography using silica gel, eluting with a 3:17 mixture of methanol and ethyl acetate to give 30 mg (yield 40%) of 7-hydroxymethylimidazo[5,1-b]thiazole.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[N:22]([CH:26]([CH3:28])[CH3:27])[C:21]([C:29]([OH:31])=O)=[CH:20]3)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:32]([O:34][C:35]([N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)=[O:36])[CH3:33].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[N:22]([CH:26]([CH3:27])[CH3:28])[C:21]([C:29]([N:40]2[CH2:39][CH2:38][N:37]([C:35]([O:34][CH2:32][CH3:33])=[O:36])[CH2:42][CH2:41]2)=[O:31])=[CH:20]3)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOC(=O)N1CCNCC1
Reactant: CC(C)n1c(C(=O)O)cc2cc(C(=O)N3CCCN(C(=O)OC(C)(C)C)CC3)ccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Product: CCOC(=O)N1CCN(C(=O)c2cc3cc(C(=O)N4CCCN(C(=O)OC(C)(C)C)CC4)ccc3n2C(C)C)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 102.2 %

Procedure:
To a mixture of 5-(4-tert-butoxycarbonyl-[1,4]diazepane-1-carbonyl)-1-isopropyl-1H-indole-2-carboxylic acid (144 mg) and 4-ethoxy carbonyl piperazine (1 eq., 53 mg) in acetonitrile (5 ml) was added N-hydroxybenzotriazole (0.2 eq., 9 mg). The mixture was stirred 5 min before the addition of N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochloride (1.1 eq., 77 mg). The mixture was stirred two days at room temperature. The mixture was evaporated under reduced pressure and the residue purified by column chromatography on silica gel (19:1 EtOAc/MeOH) to afford the product as an off-white powder (195 mg, 89%). MS (m/z): 570.3 (M+H)+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[OH:15][CH2:16][C@H:17]([NH:25][C:26](=[O:30])[C:27](O)=[O:28])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:27](=[O:28])[C:26]([NH:25][C@H:17]([CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH2:16][OH:15])=[O:30]
Reactant: O=C(O)C(=O)N[C@@H](CO)Cc1ccccc1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)C(=O)N[C@@H](CO)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.5 %

Procedure:
The mixture of 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.210 g; 0.890 mmol), (R)-2-(1-hydroxy-3-phenylpropan-2-ylamino)-2-oxoacetic acid (0.219 g; 0.979 mmol), HATU (0.339 g: 0.890 mmol) and N,N-diisopropylethylamine (0.389 mL; 2.23 mmol) in DMF (5 mL) was stirred at room temperature overnight and concentrated under reduced pressure. The residue was dissolved in dichloromethane, the organic layer was washed with water and was concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (eluent 1 to 10% methanol in dichloromethane) to yield 0.226 g (63%) of (R)-N1-(2-(5-chloro-1H-indol-3-yl)ethyl)-N2-(1-hydroxy-3-phenylpropan-2-yl)oxalamide as a white solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]=[C:7]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:6]=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C(#N)C>[CH3:26][S:27]([O:1][CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([NH:9][C:10]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:16])[N:8]=1)(=[O:29])=[O:28]
Reactant: CC(C)(C)OC(=O)Nc1cccc(CO)n1
Reactant: CS(=O)(=O)Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)Nc1cccc(COS(C)(=O)=O)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 6-(hydroxymethyl)pyridin-2-ylcarbamate 78 (3.0 g, 13.4 mmol) and diisopropylethylamine (5.0 g, 40 mmol) in acetonitrile (30 mL) was added methanesulfonyl chloride (2.0 g, 17.4 mmol) over a period of 30 min at 0° C. and the mixture was stirred for 2 h at room temperature. The reaction was quenched by adding saturated aqueous NaHCO3 and extracted with ethyl acetate (3×60 mL). The combined organic layers were washed with brine, dried (Na2SO4) and concentrated under reduced pressure to afford quantitative yield of crude 79.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.[CH2:25]([NH:32][C:33](=[S:36])[NH:34][NH2:35])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O>CCO>[CH2:25]([NH:32][C:33]([NH:34][N:35]=[CH:19][C:18]1[CH:21]=[CH:22][C:15]([C:12]2[N:13]=[CH:14][N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:24])([F:23])[F:1])=[CH:5][CH:6]=3)[N:11]=2)=[CH:16][CH:17]=1)=[S:36])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=Cc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: NNC(=S)NCc1ccccc1
Solvent: O
Solvent: CCO
Product: FC(F)(F)Oc1ccc(-n2cnc(-c3ccc(C=NNC(=S)NCc4ccccc4)cc3)n2)cc1
Temperature: 80 °C

Procedure:
To a 50 mL round-bottomed flask containing 4-[1-[4-(trifluoromethoxy)phenyl]-1,2,4-triazol-3-yl]benzaldehyde (500 mg, 1.5 mmol) in EtOH (3 mL) was added 4-benzylthiosemicarbazide (650 mg, 3.6 mmol). The reaction mixture was heated at 80° C. overnight. H2O was added upon completion of the reaction, and the crude product material was isolated by vacuum filtration. The title compound was isolated via RP-HPLC as a white solid (390 mg, 52%): mp 220-224° C.; 1H NMR (400 MHz, CDCl3) δ 9.29 (s, 1H), 8.59 (s, 1H), 8.21 (d, J=8.4 Hz, 2H), 7.85-7.79 (m, 3H), 7.71 (d, J=8.4 Hz, 2H), 7.46-7.30 (m, 8H), 5.01 (d, J=5.8 Hz, 2H); ESIMS m/z 497.2 (M+H).
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:6]2[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=2[S:4][CH2:3]1.Br[CH:23]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][N:34]1[C:38](=[O:39])[C:37]2=[CH:40][CH:41]=[CH:42][CH:43]=[C:36]2[C:35]1=[O:44])[C:24]([O:26][CH2:27][CH3:28])=[O:25].C(N(CC)CC)C>C(#N)C>[CH2:27]([O:26][C:24]([C@H:23]([NH:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])[C:6]2[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=2[S:4][CH2:3]1)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][N:34]1[C:35](=[O:44])[C:36]2=[CH:43][CH:42]=[CH:41][CH:40]=[C:37]2[C:38]1=[O:39])=[O:25])[CH3:28]
Reactant: CC(C)(C)OC(=O)CN1C(=O)[C@@H](N)CSc2ccccc21
Reactant: CCOC(=O)C(Br)CCCCCN1C(=O)c2ccccc2C1=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)[C@@H](CCCCCN1C(=O)c2ccccc2C1=O)N[C@H]1CSc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Yield: 25.3 %

Procedure:
In 100 ml of acetonitrile are dissolved 2 g of tert-butyl 3(R)-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate and 7.4 g of ethyl 2-bromo-7-phthalimidoheptanoate, and 0.85 g of triethylamine is added to the solution. After the mixture is heated at 80°-100° C. for 2 days, the mixture is concentrated under reduced pressure, diluted with 100 ml of water and extracted with 200 ml of ethyl acetate. The ethyl acetate layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting oily substance is separated and purified by silicagel column chromatography (hexane:ethyl acetate=2:1) to give from the first fraction 1.0 g of tert-butyl 3(R)-[1(R)-ethoxycarbonyl6-phthalimidohexyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate as a colorless oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([S:12](Cl)(=[O:14])=[O:13])=[C:7]([CH3:16])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:17][C:18]1[C:24]([C:25]([F:28])([F:27])[F:26])=[CH:23][C:22]([C:29]([F:32])([F:31])[F:30])=[CH:21][C:19]=1[NH2:20]>N1C=CC=CC=1>[C:1]([C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([S:12]([NH:20][C:19]2[CH:21]=[C:22]([C:29]([F:30])([F:31])[F:32])[CH:23]=[C:24]([C:25]([F:26])([F:27])[F:28])[C:18]=2[CH3:17])(=[O:14])=[O:13])=[C:7]([CH3:16])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C(C)(C)C)cc(C)c1S(=O)(=O)Cl
Reactant: Cc1c(N)cc(C(F)(F)F)cc1C(F)(F)F
Solvent: c1ccncc1
Product: Cc1cc(C(C)(C)C)cc(C)c1S(=O)(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 28.5 %

Procedure:
4-Tert-butyl-2,6-dimethyl-benzenesulfonyl chloride (0.100 g, 0.383 mmol) was added to a solution of 2-methyl-3,5-bis(trifluoromethyl)aniline (0.094 g, 0.387 mmol) in dry pyridine (1 mL). The reaction was capped and stirred at room temperature for 1 day then stirred at 30° C. for 1 day. The reaction was then concentrated under vacuum. To this was added diethyl ether (60 mL) and the mixture was washed with 0.1 N HCl (3×20 mL) followed by 0.1 N NaOH (2×20 mL) then saturated NaCl (2×20 mL). After drying the organic layer over MgSO4, the solution was filtered and concentrated under vacuum. The crude compound was triturated with hexanes (3×10 mL) to afford the title compound (0.051 g, 28% yield). LCMS (M+Na) 490.
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=2)=[CH:4][N:3]=[CH:2]1.[Li]CCCC.[C:17](Cl)(=[O:20])[CH2:18][CH3:19]>C1COCC1.CCOC(C)=O.[Cl-].[Cl-].[Zn+2]>[N:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C:5]1[O:1][C:2]([C:17](=[O:20])[CH2:18][CH3:19])=[N:3][CH:4]=1
Reactant: CCC(=O)Cl
Reactant: c1ccc(-c2cnco2)nc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC(=O)c1ncc(-c2ccccn2)o1
Reaction time: 0.33 h
Yield: 65.7 %

Procedure:
(194) A solution of 2-(oxazol-5-yl)pyridine (98 mg, 0.67 mmol) in anhydrous THF (5 mL) cooled to −75° C. under N2 was treated with n-BuLi (2.5 M in hexanes, 1.1 equiv, 0.74 mmol, 0.3 mL), and stirred for 20 min. ZnCl2 (0.5 M in THF, 2.0 equiv, 1.34 mmol, 2.7 mL) was added at −75° C., and stirred for 45 min at 0° C. Cul (1.0 equiv, 0.67 mmol, 128 mg) was added, and the solution was stirred for 10 min at 0° C. Propionyl chloride (2.0 equiv, 1.34 mmol, 124 mg, 0.12 mL) was added and the solution was stirred for 1 h at 0° C. The reaction was diluted with EtOAc (10 mL), and washed with 15% aqueous NH4OH (1×10 mL), H2O (1×10 mL), and saturated aqueous NaCl (1×10 mL). The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. Flash chromatography (SiO2, 2.5 cm×17.5 cm, 20% EtOAc-hexanes) afforded 1-[5-(pyridin-2-yl)oxazol-2-yl]propan-1-one (194) (89 mg, 0.44 mmol, 65% yield) as a light brown powder: mp 65-67° C.; 1H NMR (CDCl3, 250 MHz) d 8.65-8.62 (m, 1H), 7.86-7.75 (m, 3H), 7.31-7.26 (m, 1H), 3.18-3.08 (m, 2H), 1.29-1.21 (m, 3H); 13C NMR (CDCl3, 62.5 MHz) d 188.8, 161.9, 157.2, 150.1, 146.3, 136.9, 126.8, 124.0, 120.3, 32.5, 7.8; IR (KBr) u. 2935, 2862, 1699, 1471, 1426, 1377 cm−1; MALDI-FTMS (DHB) m/z 203.0818 (C11H10N2O2+H+ requires 203.0815).
Reaction SMILES: [NH2:1][C:2](=[C:12](C(OC)=O)[C:13]([O:15][CH3:16])=[O:14])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=1.[OH-].[K+]>CO.O>[NH2:1][C:2]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=1)=[CH:12][C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)C(C(=O)OC)=C(N)c1cccc([N+](=O)[O-])c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)C=C(N)c1cccc([N+](=O)[O-])c1
Yield: 52.8 %

Procedure:
A mixture of dimethyl (α-amino-3-nitrobenzylidene)-malonate (120 g) and potassium hydroxide in a mixture of methanol (1.2 l) and water(120 ml) was refluxed for 8 hours. The reaction mixture was concentrated under reduced pressure to a volume of 200 ml. The resulting crystals were collected by filtration and recrystallized from methanol to give methyl 3-amino-3-(3-nitrophenyl)-acrylate (50.2 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([C:17]2[C:18]([CH3:29])=[N:19][O:20][C:21]=2[C:22]2[CH:27]=[CH:26][C:25](Br)=[CH:24][CH:23]=2)[OH:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:30]([O:32][C:33]([C:35]1([C:38]2[CH:43]=[CH:42][C:41](B3OC(C)(C)C(C)(C)O3)=[CH:40][CH:39]=2)[CH2:37][CH2:36]1)=[O:34])[CH3:31]>>[CH2:30]([O:32][C:33]([C:35]1([C:38]2[CH:43]=[CH:42][C:41]([C:25]3[CH:26]=[CH:27][C:22]([C:21]4[O:20][N:19]=[C:18]([CH3:29])[C:17]=4[CH:15]([C:12]4[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)=[CH:10][CH:11]=4)[OH:16])=[CH:23][CH:24]=3)=[CH:40][CH:39]=2)[CH2:36][CH2:37]1)=[O:34])[CH3:31]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)c1ccc(OCc2ccccc2)cc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)c4ccc(OCc5ccccc5)cc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 42, Step 2, using (4-benzyloxy-phenyl)-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-methanol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][N:12]([CH:15]([CH2:19][C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[C:16](O)=[O:17])[C:11](=[O:26])[CH:10]=1.[NH2:27][C:28]1[CH:40]=[CH:39][C:31]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[CH:30][CH:29]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][N:12]([CH:15]([CH2:19][C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[C:16]([NH:27][C:28]2[CH:40]=[CH:39][C:31]([C:32]([O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[O:33])=[CH:30][CH:29]=2)=[O:17])[C:11](=[O:26])[CH:10]=1
Reactant: O=C(O)C(Cc1ccncc1)n1ccc(-c2cc(Cl)ccc2Br)cc1=O
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Product: CC(C)(C)OC(=O)c1ccc(NC(=O)C(Cc2ccncc2)n2ccc(-c3cc(Cl)ccc3Br)cc2=O)cc1

Procedure:
1.8 g (purity 76%, 3.2 mmol) of 2-[4-(2-bromo-5-chlorophenyl)-2-oxopyridin-1(2H)-yl]-3-(pyridin-4-yl)propanoic acid (racemate) and 1.1 eq. of tert-butyl 4-aminobenzoate were reacted according to General Method 5A. Yield: 734 mg (purity 92%, 35% of theory)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH2:13][CH2:14][CH3:15])[N:6]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]3[N:33]([C:34]([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[N:32]=[N:31][N:30]=3)=[CH:19][CH:18]=1)[C:5]2=[O:53].[CH:54]([N:57]=[C:58]=[O:59])([CH3:56])[CH3:55]>C(Cl)Cl.CCOC(C)=O>[CH2:12]([C:7]1[N:6]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]3[N:33]([C:34]([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)([C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=4)[C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)[N:32]=[N:31][N:30]=3)=[CH:21][CH:22]=2)[C:5](=[O:53])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([NH:1][C:58](=[O:59])[NH:57][CH:54]([CH3:56])[CH3:55])[CH:3]=2)[N:8]=1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCc1nc2ccc(N)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)N=C=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCCc1nc2ccc(NC(=O)NC(C)C)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reaction time: 72 h
Yield: 70 %

Procedure:
To solution of 0.069 g (0.1 mmol) of the aminoquinazolinone from Example 40 in 1 mL of CH2Cl2 was added 12.7 mg (0.15 mmol) of isopropylisocyanate. The reaction mixture was stirred for 3 days. The mixture was diluted with 20 mL of EtOAc, washed with water (2×5 mL), brine (1×5 mL) and dried over MgSO4. The mixture was filtered and concentrated in vacuo and the residue was purified by MPLC over a silica Lobar B column eluting with 50% EtOAc/hexanes to give 59.5 mg (0.07 mmol) of an oil, 76% yield. 1H-NMR (CDCl3 300 MHz): 0.86 (t, 3H, J=7.3 Hz), 1.07 (d, 6H, J=6.5 Hz), 1.29 (m, 2H), 1.68 (m, 2H), 2.59 (3 line m, 2H, J=7.06 Hz), 3.95 (m, 1H), 5.18 (d, 1H,J=7.7 Hz), 5.28 (bs, 2H), 7.12 (m, 6H), 7.07 (d, 2H), 7.19-7.32 (m, 11H), 7.43 (m, 2H), 7.57 (m, 2H), 7.90 (m, 2H), 8.13 (m, 1H).
Reaction SMILES: Cl.Cl.[CH3:3][N:4]1[CH2:8][CH2:7][C:6]2([CH2:12][CH2:11][NH:10][CH2:9]2)[CH2:5]1.N12CCCN=C1CCCCC2.[CH2:24]([N:26]1[C:35]2[C:30](=[CH:31][C:32]([F:38])=[C:33](F)[C:34]=2[F:36])[C:29](=[O:39])[C:28]([C:40]([OH:42])=[O:41])=[CH:27]1)[CH3:25]>C(#N)C>[CH2:24]([N:26]1[C:35]2[C:30](=[CH:31][C:32]([F:38])=[C:33]([N:10]3[CH2:11][CH2:12][C:6]4([CH2:7][CH2:8][N:4]([CH3:3])[CH2:5]4)[CH2:9]3)[C:34]=2[F:36])[C:29](=[O:39])[C:28]([C:40]([OH:42])=[O:41])=[CH:27]1)[CH3:25]
Reactant: CN1CCC2(CCNC2)C1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCC4(CCN(C)C4)C3)c(F)c21
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 74.1 %

Procedure:
A suspension of 0.64 g (3.0 mmol) 2-methyl-2,7-diazaspiro[4.4]nonane dihydrochloride in 40 ml acetonitrile was treated with 1.33 g (9.0 mmol) 1,8-diazabicyclo[5.4.0]undec-7-ene and 0.81 g (3.0 mmol) 1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid was added. The mixture was stirred 45 minutes at room temperature, refluxed 1.5 hours, and stirred at room temperature overnight. The precipitate was filtered and washed with acetonitrile and ether to afford 0.87 g of the title compound, mp 229°-231° C. (dec).
Reaction SMILES: [F:1][C:2]([C:5]1[N:10]=[CH:9][C:8]([CH:11]([N:14]2[CH2:19][CH2:18][C:17]([F:21])([F:20])[CH2:16][CH2:15]2)[CH2:12][NH2:13])=[CH:7][N:6]=1)([F:4])[CH3:3].[Cl:22][C:23]1[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26].C1COCC1.CCN(C(C)C)C(C)C>>[Cl:22][C:23]1[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][C:24]=1[C:25]([NH:13][CH2:12][CH:11]([C:8]1[CH:7]=[N:6][C:5]([C:2]([F:1])([F:4])[CH3:3])=[N:10][CH:9]=1)[N:14]1[CH2:19][CH2:18][C:17]([F:20])([F:21])[CH2:16][CH2:15]1)=[O:26]
Reactant: O=C(Cl)c1cccc(Cl)c1Cl
Reactant: CC(F)(F)c1ncc(C(CN)N2CCC(F)(F)CC2)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(F)(F)c1ncc(C(CNC(=O)c2cccc(Cl)c2Cl)N2CCC(F)(F)CC2)cn1
Yield: 47.4 %

Procedure:
2-(2-(1,1-Difluoroethyl)pyrimidin-5-yl)-2-(4,4-difluoropiperidin-1-yl)ethanamine (34 mg, 0.044 mmol, 40% pure) and 2,3-dichlorobenzoyl chloride (65 mg, 0.31 mmol), was dissolved in anhydrous THF (4400 mg, 5 ml, 61.0 mmol), DIPEA (111 mg, 0.15 ml, 0.859 mmol) was added and stirred over night. The solution was concentrated and purified by column chromatography on silica gel (petroleum ether: EtOAc=1:0 to 0:1) followed by HPLC, to afford 2,3-dichloro-N-(2-(2-(1,1-difluoroethyl)pyrimidin-5-yl)-2-(4,4-difluoropiperidin-1-yl)ethyl)benzamide (10 mg, 47% yield).
Reaction SMILES: O[CH:2]([C:4]1[CH:5]=[C:6]([C:10]([O:12][CH3:13])=[O:11])[CH:7]=[CH:8][CH:9]=1)[CH3:3].P(Br)(Br)[Br:15]>C1(C)C=CC=CC=1>[Br:15][CH:2]([C:4]1[CH:5]=[C:6]([C:10]([O:12][CH3:13])=[O:11])[CH:7]=[CH:8][CH:9]=1)[CH3:3]
Reactant: COC(=O)c1cccc(C(C)O)c1
Reactant: BrP(Br)Br
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(C(C)Br)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
5 g (27.75 mmol) of methyl 3-(1-hydroxyethyl)benzenecarboxylate (Example 60A) were initially charged in 100 ml of toluene. At 0° C., 0.98 g (36.07 mmol) of phosphorus tribromide were added dropwise, and the mixture was stirred at RT for 45 min. The reaction solution was poured onto ice-water and extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and evaporated. The residue was purified by column chromatography on silica gel 60 (mobile phase:cyclohexane:ethyl acetate 50:1→40:1).
Reaction SMILES: C([O:3][C:4](=[O:20])[C:5]([S:8]([C:11]1[CH:19]=[CH:18][C:14]2[N:15]=[CH:16][S:17][C:13]=2[CH:12]=1)(=[O:10])=[O:9])([CH3:7])[CH3:6])C.O.[OH-].[Li+]>O1CCOCC1.O>[S:17]1[C:13]2[CH:12]=[C:11]([S:8]([C:5]([CH3:7])([CH3:6])[C:4]([OH:20])=[O:3])(=[O:10])=[O:9])[CH:19]=[CH:18][C:14]=2[N:15]=[CH:16]1
Reactant: CCOC(=O)C(C)(C)S(=O)(=O)c1ccc2ncsc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C(=O)O)S(=O)(=O)c1ccc2ncsc2c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 96.9 %

Procedure:
To a solution of 778 mg (2.48 mmol) of 2-(benzothiazole-6-sulfonyl)-2-methyl-propionic acid ethyl ester in THF/water (1/1, 24 mL) are added 208 mg (4.97 mmol) of lithium hydroxide monohydrate. The reaction is stirred at room temperature for 5 h. The organic solvent is removed under reduced pressure. The basic aqueous layer is washed with diethyl ether (10 mL), then cooled in an ice bath and acidified with 6M aqueous HCl solution to pH 2. The acidic aqueous layer is extracted with ethyl acetate (3×15 mL). The combined organic extracts are dried over Na2SO4 and filtered. Concentration of the filtrate under reduced pressure afforded 686 mg of 2-(benzothiazole-6-sulfonyl)-2-methyl-propionic acid as a pale yellow solid. Yield: 66%; ES-MS: m/z 569 [2M−H]; 1H NMR (250 MHz, DMSO-d6) δ ppm 1.51 (6H, s), 7.91 (1H, dd, J=8.68, 1.98 Hz), 8.30 (1H, d, J=8.68 Hz), 8.79 (1H, d, J=1.83 Hz), 9.70 (1H, s);
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[O:11][N:10]=[C:9]([C:12]([OH:14])=O)[CH:8]=2)[CH:4]=[N:3]1.C1C=CC2N(O)N=NC=2C=1.N=C=N.[NH2:28][C@@H:29]([CH3:45])[CH2:30][N:31]1[CH:35]=[CH:34][C:33]([C:36]2[CH:43]=[CH:42][C:39]([C:40]#[N:41])=[C:38]([CH3:44])[CH:37]=2)=[N:32]1.C(O)C(N)(CO)CO>CN(C=O)C.C(Cl)Cl>[C:40]([C:39]1[CH:42]=[CH:43][C:36]([C:33]2[CH:34]=[CH:35][N:31]([CH2:30][C@@H:29]([NH:28][C:12]([C:9]3[CH:8]=[C:7]([C:5]4[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=4)[O:11][N:10]=3)=[O:14])[CH3:45])[N:32]=2)=[CH:37][C:38]=1[CH3:44])#[N:41]
Reactant: Cc1cc(-c2ccn(C[C@H](C)N)n2)ccc1C#N
Reactant: Cn1cc(-c2cc(C(=O)O)no2)cn1
Agent: N=C=N
Agent: NC(CO)(CO)CO
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cc(-c2ccn(C[C@H](C)NC(=O)c3cc(-c4cnn(C)c4)on3)n2)ccc1C#N
Reaction time: 24 h
Yield: 18.1 %

Procedure:
5-(1-methyl-1H-pyrazol-4-yl)isoxazole-3-carboxylic acid (57.9 mg, 0.3 mmol), HOBt (46 mg, 0.340 mmol) and PS-carbodiimide (364 mg), DCM (4 ml) and DMF (0.4 ml) were mixed in a glass vial. The mixture was shaken for 10 min. (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-methylbenzonitrile (48 mg, 0.2 mmol) was added and the mixture was stirred for 24 h. The solids were filtered off PS-Trisamine (333 mg, 1.0 mmol) was added to the filtrate. The mixture was shaken for 4 h and filtered. The filtrate was concentrated and purified by flash chromatography (gradient of DCM:MeOH) to give 15 mg of the title compound. 1H-NMR (400 MHz; CDCl3): δ 1.25 (d, 3H), 4.00 (s, 3H), 4.23-4.28 (m, 1H), 4.42-4.49 (m, 1H), 4.55-4.66 (m, 1H), 6.62 (d, 1H), 6.67 (s, 1H), 7.49 (d, 1H), 7.63 (d, 1H), 7.72-7.75 (m, 1H), 7.81 (m, 2H), 7.96 (s, 1H), 8.14 (m, 1H).