Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)CCCNC(NC1SC(C2C=CC(S(C)(=O)=O)=C(F)C=2)=C(C)N=1)=O)C.[NH2:30][C:31]1[S:32][C:33]([C:37]2[CH:42]=[C:41]([Cl:43])[C:40]([S:44]([N:47]([CH3:49])[CH3:48])(=[O:46])=[O:45])=[C:39]([Cl:50])[CH:38]=2)=[C:34]([CH3:36])[N:35]=1.[CH2:51]([O:53][C:54](=[O:60])[CH2:55][CH2:56][N:57]=[C:58]=[O:59])[CH3:52]>>[CH2:51]([O:53][C:54](=[O:60])[CH2:55][CH2:56][NH:57][C:58]([NH:30][C:31]1[S:32][C:33]([C:37]2[CH:42]=[C:41]([Cl:43])[C:40]([S:44](=[O:46])(=[O:45])[N:47]([CH3:49])[CH3:48])=[C:39]([Cl:50])[CH:38]=2)=[C:34]([CH3:36])[N:35]=1)=[O:59])[CH3:52]
Reactant: Cc1nc(N)sc1-c1cc(Cl)c(S(=O)(=O)N(C)C)c(Cl)c1
Reactant: CCOC(=O)CCN=C=O
Agent: CCOC(=O)CCCNC(=O)Nc1nc(C)c(-c2ccc(S(C)(=O)=O)c(F)c2)s1
Product: CCOC(=O)CCNC(=O)Nc1nc(C)c(-c2cc(Cl)c(S(=O)(=O)N(C)C)c(Cl)c2)s1

Procedure:
The title compound is prepared by the same procedure as 4-{3-[5-(3-Fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-ureido}-butyric acid ethyl ester (Example 164) by replacing 5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine (Example 72) with 4-(2-amino-4-methyl-thiazol-5-yl)-2,6-dichloro-N,N-dimethyl-benzenesulfonamide (171b) and replacing ethyl-4-isocyanatobutyrate with 3-isocyanato-propionic acid ethyl ester.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[C:13]([Cl:20])[CH:12]=1)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:21]1([NH2:26])[CH2:25][CH2:24][CH2:23][CH2:22]1.CCN=C=NCCCN(C)C.Cl.ON1C2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C>O.CN(C=O)C>[Cl:20][C:13]1[CH:12]=[C:11]([C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH3:10])[CH:19]=[CH:18][C:14]=1[C:15](=[O:17])[NH:26][CH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: NC1CCCC1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(C(=O)O)c(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](NC(=O)OC(C)(C)C)c1ccc(C(=O)NC2CCCC2)c(Cl)c1
Yield: 97.5 %

Procedure:
To a round bottom flask with stir bar was added (S)-4-(1-(tert-butoxycarbonylamino)ethyl)-2-chlorobenzoic acid (450 mg, 1.20 mmol), cyclopentylamine (355 μL, 3.60 mmol), EDC HCl (460 mg, 2.40 mmol), 1-hydroxy-7-aza-benzotriazole (229 mg, 1.68 mmol) and DMF (6 mL). To this mixture was then added DIEA (629 μL, 3.60 mmol). Reaction mixture was allowed to stir at room temperature for 18 hours. The reaction mixture was diluted with water and extracted with EtOAc. The organic phases were combined, washed with twice with water, brine, dried (Na2SO4), filtered and concentrated to a brown crystalline of (S)-tert-butyl 1-(3-chloro-4-(cyclopentylcarbamoyl)phenyl)ethylcarbamate (476 mg, 1.17 mmol, 97% yield). LCMS m/z 367.0 (M+H)+, Rt 0.90 min.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])=[CH:13][N:12]2[C:23]([NH2:26])=[N:24][N:25]=[C:11]2[CH:10]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH2:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])=[CH:13][N:12]2[C:23]([NH2:26])=[N:24][N:25]=[C:11]2[CH:10]=1
Reactant: CC(C)(C)OC(=O)NCc1cc2nnc(N)n2cc1-c1ccc(Cl)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCc1cc2nnc(N)n2cc1-c1ccc(Cl)cc1Cl
Yield: 26.2 %

Procedure:
[3-Amino-6-(2,4-dichloro-phenyl)-[1,2,4]triazolo[4,3-a]pyridin-7-ylmethyl]-carbamic acid tert-butyl ester (17 mg, 0.042 mmol) was dissolved in DCM (2 mL) and TFA (1 mL) and the solution was stirred at RT for 30 min. The reaction mixture was concentrated to dryness and the remaining residue purified by reverse phase prep-HPLC (Waters system) to give the title compound (2TFA salt, 5.7 mg, 0.011 mmol, 26%) as a white solid. MS: 308 [M+1]+; HPLC: AtRet=0.77.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][CH2:12][C:13]1[O:14][C:15]([CH2:21][OH:22])=[C:16]([OH:20])[C:17](=[O:19])[CH:18]=1)(=[O:10])=[O:9].[CH2:23](OC1C(=O)C=C(CNS(C2C=CC=CC=2)(=O)=O)OC=1CO)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([O:20][C:16]1[C:17](=[O:19])[CH:18]=[C:13]([CH2:12][NH:11][S:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])(=[O:9])=[O:10])[O:14][C:15]=1[CH2:21][OH:22])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=c1cc(CNS(=O)(=O)c2ccccc2)oc(CO)c1OCc1ccccc1
Reactant: O=c1cc(CNS(=O)(=O)c2ccccc2Cl)oc(CO)c1O
Product: O=c1cc(CNS(=O)(=O)c2ccccc2Cl)oc(CO)c1OCc1ccccc1
Yield: 35 %

Procedure:
N-(5-Benzyloxy-6-hydroxymethyl-4-oxo-4H-pyran-2-ylmethyl)-2-chloro-benzenesulfonamide (10-03) (3.5 g, 35.0%) was synthesized as a white solid from 2-chloro-N-(5-hydroxy-6-hydroxymethyl-4-oxo-4H-pyran-2-ylmethyl)-benzenesulfonamide (9-03) (8.0 g, 23.18 mmol) following the procedure described for N-(5-benzyloxy-6-hydroxymethyl-4-oxo-4H-pyran-2-ylmethyl)-benzenesulfonamide (10-01).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][C@@H:27]1[C:32]([O:34][CH3:35])=[O:33].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl.O>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:13]([N:26]1[CH2:31][CH2:30][CH2:29][CH2:28][C@@H:27]1[C:32]([O:34][CH3:35])=[O:33])=[O:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: COC(=O)[C@H]1CCCCN1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Solvent: O
Product: COC(=O)[C@H]1CCCCN1C(=O)[C@H](CNC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 69.7 %

Procedure:
To a suspension of (S)-2-(benzyloxycarbonylamino)-3-(tert-butoxycarbonylamino)propanoic acid (2.26 g, 6.68 mmol) in DCM (50 mL) was added (R)-methyl piperidine-2-carboxylate HCl salt (1.00 g, 5.57 mmol), followed by EDC (1.60 g, 8.35 mmol), HOBT (1.71 g, 11.1 mmol), and TEA (2.33 mL, 16.7 mmol). The reaction mixture was stirred at rt for 6 hr. The reaction mixture was diluted with water and extracted with EtOAc (2×30 mL). The combined EtOAc layers were washed with water and saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated. The crude product was purified using silica gel chromatography (ISCO system) eluting with a gradient of 30-70% EtOAc/Hex to give (R)-methyl 1-((S)-2-(benzyloxycarbonylamino)-3-(tert-butoxycarbonylamino)propanoyl)piperidine-2-carboxylate (1.80 g, 3.88 mmol, 69.8% yield) as a white foam. Anal. Calcd. for C23H33N3O7 m/z 463.5. found: 464.3 (M+H)+.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].Cl.[CH2:6]1[O:16][C:9]2([CH2:14][CH2:13][CH2:12][CH2:11][C:10]2=O)[O:8][CH2:7]1.C([BH3-])#N.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CO.O>[CH2:6]1[O:16][C:9]2([CH2:14][CH2:13][CH:12]([NH:4][CH2:1][CH2:2][CH3:3])[CH2:11][CH2:10]2)[O:8][CH2:7]1
Reactant: O=C1CCCCC12OCCO2
Reactant: CCCN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [BH3-]C#N
Solvent: CO
Solvent: O
Product: CCCNC1CCC2(CC1)OCCO2
Temperature: 2.5 °C
Reaction time: 0.25 h

Procedure:
A mixture of n-propyl amine (162 ml, 1.474 mol) in methanol (500 ml) was chilled to 0-5° C. To this solution was added methanolic hydrochloric acid (155 ml, 44.47%) dropwise over a period of 30 minutes to achieve a pH of 6-7. Cyclohexandione monoethyleneketal 1 (100 g, 0.641 mol) was charged at 5° C. and the reaction was stirred for 15 minutes. Sodium cyanoborohydride (60 g, 0.952 mol) was added in 15 minutes at 5° C. The pH increased to about 8 and methanolic hydrochloric acid (15 ml, 44.47%) was added to bring the pH to 6-7. The reaction was allowed to come to 24-26° C. Stirring was continued for 2 hours. Methanol was distilled off (450 ml). Sodium carbonate (95 g, 0.896 mol) was dissolved in water (850 ml) and charged to the reaction mass at ambient temperature in one shot. The reaction mass was extracted with dichloromethane (2500 ml). The dichloromethane layers were combined and dried over sodium sulfate (8.5 g). The dichloromethane layer was concentrated to dryness at 40° C. and 15 mbar pressure. The product 2 was light yellow viscous oil. The weight of the product 2 obtained was 135 g (105.8%); GC purity 97.74%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:15]([C:20](O)=[O:21])=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:10][C:9]=2[F:23])=[CH:4][N:3]=1.[NH:24]1[CH2:29][CH2:28][CH:27]([NH2:30])[CH2:26][CH2:25]1>>[NH2:30][CH:27]1[CH2:28][CH2:29][N:24]([C:20]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[C:11]2[CH:12]=[CH:13][C:8]([C:5]3[N:6]=[CH:7][C:2]([NH2:1])=[N:3][CH:4]=3)=[C:9]([F:23])[CH:10]=2)=[O:21])[CH2:25][CH2:26]1
Reactant: NC1CCNCC1
Reactant: Nc1cnc(-c2ccc(-c3ccccc3C(=O)O)cc2F)cn1
Product: Nc1cnc(-c2ccc(-c3ccccc3C(=O)N3CCC(N)CC3)cc2F)cn1

Procedure:
The title compound was prepared using methods analogous to those described in Step C of Example 504 using 4′-(2-aminopyrazin-5-yl)-3′-fluoro-[1,1′-biphenyl]-2-carboxylic acid and piperidin-4-amine. MS (ESI): mass calcd. for C22H22FN5O, 391.18; m/z found, 392.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.34 (s, 1H), 7.99 (s, 1H), 7.88 (s, 1H), 7.48 (d, J=14.8, 3H), 7.35-7.20 (m, 3H), 6.69 (s, 2H), 4.31 (s, 1H), 3.08-2.50 (m, 6H), 1.75 (t, J=80.9, 2H), 1.38-0.86 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:36])[N:10]2[CH2:13][CH2:14][CH2:15][C:16]2([C:31]([O:33]CC)=[O:32])[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:18][CH2:17]2)=[CH:5][CH:4]=1.[OH-].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:36])[N:10]2[CH2:13][CH2:14][CH2:15][C:16]2([C:31]([OH:33])=[O:32])[CH2:17][CH2:18][N:19]([CH2:22][CH2:23][O:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:20][CH2:21]2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)C1(CCCn2c(=O)ccc3ccc(OC)cc32)CCN(CCOc2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc2ccc(=O)n(CCCC3(C(=O)O)CCN(CCOc4ccccc4)CC3)c2c1
Temperature: 25 °C
Yield: 76.9 %

Procedure:
To 1.5 mL of an ethanol solution containing 0.12 g of ethyl 4-(3-(7-methoxy-2-oxo-1,2-dihydroquinolin-1-yl)propyl)-1-(2-phenoxyethyl)piperidine-4-carboxylate, 0.7 mL of 20% aqueous sodium hydroxide solution was added at room temperature and refluxed with heating for 4.5 hours. After the reaction mixture was cooled to the room temperature, the solvent was removed under reduced pressure, water was added, adjusted to pH 6.5 with 6.0 mol/L hydrochloric acid. The resulting solid was filtered to give 87 mg of 4-(3-(7-methoxy-2-oxo-1,2-dihydroquinolin-1-yl)propyl)-1-(2-phenoxyethyl)piperidine-4-carboxylic acid as a pale yellow solid.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[N:24]([CH3:29])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:30].[N:31]1([CH2:37][CH2:38][NH:39][C:40]2[CH:45]=[CH:44][C:43]([NH2:46])=[CH:42][CH:41]=2)[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>C1COCC1>[N:31]1([CH2:37][CH2:38][NH:39][C:40]2[CH:45]=[CH:44][C:43]([NH:46][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][C:8]([C:12]([C:14]5[CH:15]=[C:16]([NH:20][C:21]([C:23]6[N:24]([CH3:29])[N:25]=[C:26]([CH3:28])[CH:27]=6)=[O:22])[CH:17]=[CH:18][CH:19]=5)=[O:13])=[CH:9][CH:10]=4)[NH:5][C:4]3=[O:30])=[CH:42][CH:41]=2)[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1
Reactant: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)n(C)n1
Reactant: Nc1ccc(NCCN2CCOCC2)cc1
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3ccc(NCCN4CCOCC4)cc3)c2)n(C)n1
Temperature: 65 °C
Reaction time: 24 h
Yield: 45 %

Procedure:
A small screw cap test tube was charged with 2,5-Dimethyl-2H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 60, 100 mg, 0.249 mmol) and THF (2.5 mL). To the resulting solution was added N-(2-Morpholin-4-yl-ethyl)-benzene-1,4-diamine (prepared below, 77.1 mg, 0.348 mmol), and the mixture was stirred for 24 h at 65° C. The reaction mixture was cooled to room temperature and then diluted with Hexanes (˜40 mL). The black precipitate that formed was removed by filtration and the filtrate was concentrated in vacuo. The crude residue was dissolved in EtOAc (˜5 mL) and triturated with Hexane (˜50 mL) to give a yellow precipitate. The precipitate was filtered and washed with 0° C. i-prOH (˜5 mL) yielding 45% (0.0677 g, 0.112 mmol) of the title compound.
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:8](=[O:11])[N:7]([C:12]3[CH:23]=[CH:22][C:15]([O:16][CH2:17][C:18]([CH3:21])([OH:20])[CH3:19])=[C:14]([O:24][CH3:25])[CH:13]=3)[CH:6]=[N:5][C:4]=2[CH:3]=1.[Cl:26][C:27]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].N#N>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:26][C:27]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=1[C:2]1[S:10][C:9]2[C:8](=[O:11])[N:7]([C:12]3[CH:23]=[CH:22][C:15]([O:16][CH2:17][C:18]([CH3:21])([OH:20])[CH3:19])=[C:14]([O:24][CH3:25])[CH:13]=3)[CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: COc1cc(-n2cnc3cc(Br)sc3c2=O)ccc1OCC(C)(C)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Product: COc1cc(-n2cnc3cc(-c4ccc(Cl)cc4Cl)sc3c2=O)ccc1OCC(C)(C)O
Temperature: 110 °C
Yield: 69.5 %

Procedure:
A mixture of 1-(4-(6-bromo-4-oxo-thieno[3,2-d]pyrimidin-3(4H)-yl)-2-methoxyphenoxy)-2-methyl-2-propanol (50 mg, 0.12 mmol), 2,4-dichlorobenzeneboronic acid (21 mg, 0.18 mmol), Na2CO3 (31 mg, 0.29 mmol), tetrakis(triphenylphosphine)palladium (10 mg, 0.0088 mmol), N2-degassed dioxane (1 mL) and N2-degassed water (0.5 mL) was heated in a 110° C. bath for 30 min. The mixture, upon cooling, was poured into half-saturated NaHCO3 (3 mL). The mixture was extracted with CH2Cl2 (2×5 mL). The combined organic layers were dried (MgSO4) and concentrated in vacuo. The residue was chromatographed (4 g silica, CH2Cl2 to 50% EtOAc-CH2Cl2) to provide 1-(4-(6-(2,4-dichlorophenyl)-4-oxo-thieno[3,2-d]pyrimidin-3(4H)-yl)-2-methoxyphenoxy)-2-methyl-2-propanol as an off-white solid (41 mg, 71%). 1H-NMR (CDCl3) δ 8.09 (s, 1 H), 7.54 (s, 1 H), 7.49 (m, 2 H), 7.29 (dd, J=8, 2 Hz, 1 H), 6.84-6.96 (m, 3 H), 3.81 (s, 5 H), 1.30 (s, 6H); HPLC (Method #7) 4.2 min; LCMS (ES) m/z 491 (M+H).
Reaction SMILES: Cl.C(N[C:6](=[CH:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=1)[C:7]([OH:9])=[O:8])(=O)C.[OH2:19].C1(C)C=CC=CC=1>CN1CCCC1=O>[Cl:18][C:13]1[CH:12]=[C:11]([CH2:10][C:6](=[O:19])[C:7]([OH:9])=[O:8])[CH:16]=[CH:15][C:14]=1[Cl:17]
Reactant: O
Reactant: CC(=O)NC(=Cc1ccc(Cl)c(Cl)c1)C(=O)O
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: Cc1ccccc1
Product: O=C(O)C(=O)Cc1ccc(Cl)c(Cl)c1
Temperature: 125 °C

Procedure:
140 mL 4 M HCl were added to a suspension of 21.0 g (76.6 mmol) 2-acetylamino-3-(3,4-dichloro-phenyl)-acrylic acid in 100 mL N-methyl-2-pyrrolidinone and the reaction mixture was then heated for 4 h at an oil bath temperature of 125° C. The cooled reaction solution was poured onto a cooled mixture of 350 mL water and 120 mL toluene. The phases were separated, the aqueous phase was again extracted with toluene, the combined organic phases were extracted with water, filtered through Na2SO4 and evaporated down i. vac. The residue was taken up in 1 M NaOH and washed twice with diethyl ether. The aqueous phase was acidified with 2 M HCl and extracted three times with EtOAc. The combined organic phases were filtered through Na2SO4 and evaporated down i. vac. The residue was combined with diethyl ether, suction filtered and dried in the vacuum drying cupboard.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:16][C@@:13]3([O:15][CH2:14]3)[CH2:12][CH2:11][CH2:10]2)[C:5]([F:17])=[CH:4][N:3]=1.[C-:18]#[N:19].[Na+].Cl([O-])(=O)(=O)=O.[Li+].CCOC(C)=O>CC#N>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:10][CH2:11][CH2:12][C@:13]([CH2:14][C:18]#[N:19])([OH:15])[CH2:16]2)[C:5]([F:17])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1NC1CCC[C@@]2(CO2)C1
Reactant: [C-]#N
Agent: [Li+]
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: N#CC[C@]1(O)CCC[C@H](Nc2nc(Cl)ncc2F)C1
Temperature: 100 °C

Procedure:
A suspension of 2-chloro-5-fluoro-N-[(3S)-1-oxaspiro[2.5]octan-7-yl]pyrimidin-4-amine, 49c, (0.50 g, 1.94 mmol), NaCN (0.11 g, 2.33 mmol) and lithium perchlorate (0.25 g, 2.33 mmol) in CH3CN was heated at 100° C. in a pressure tube for 3 h. The mixture was diluted into EtOAc and the organic phase was washed with aqueous saturated NaHCO3 solution, dried with MgSO4, filtered and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel chromatography (EtOAc/hexanes) afforded the desired product: 1H NMR (300.0 MHz, CDCl3) δ 7.78 (d, J=2.7 Hz, 1H), 4.85 (d, J=6.6 Hz, 1H), 4.28 (qn, J=4.0 Hz, 1H), 2.45 (s, 2H), 2.16 (d, J=13.0 Hz, 1H), 2.05 (d, J=11.7 Hz, 1H), 1.80-1.71 (m, 3H), 1.46-1.28 (m, 2H) and 1.17-1.06 (m, 1H) ppm; LCMS RT=2.15 (M+H) 285.34.
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[C:10]([CH3:12])[N:9]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=2[F:23])[C:8](=[O:24])[CH:7]=1.[Br:30]N1C(=O)CCC1=O.C([O-])(O)=O.[Na+]>>[Br:30][C:7]1[C:8](=[O:24])[N:9]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=2[F:23])[C:10]([CH3:12])=[CH:11][C:6]=1[O:5][CH2:4][C:3]1[CH:25]=[CH:26][C:27]([F:29])=[CH:28][C:2]=1[F:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(-n2c(C)cc(OCc3ccc(F)cc3F)cc2=O)c(F)c1
Agent: O=C([O-])O
Agent: [Na+]
Product: COC(=O)c1ccc(-n2c(C)cc(OCc3ccc(F)cc3F)c(Br)c2=O)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.7 %

Procedure:
A 100 mL round bottomed flask equipped with stirbar and nitrogen inlet was charged with the product of Step 4 (2.15 g, 5.3 mmol) and N-methyl-2-pyrrolidine (15 mL). After cooling to 0 C, a solution of N-bromo succinimide (1.03 g, 5.8 mmol) in 10 mL of N-methyl-2-pyrrolidine was added over 15 minutes. After 15 additional minutes, the reaction mixture was warmed to room temperature and was stirred for 1 hour. The mixture was then poured into saturated aqueous NaHCO3 and extracted with ethyl acetate. The organic layer was washed with brine and concentrated in vacuo. The residue was triturated with acetonitrile and filtered to give the title compound as a white powder (1.5 g, 59%). 1H NMR (400 MHz, CD3OD) δ 8.00 (dd, J=2.0 and 8.4 Hz, 1H), 7.95 (dd, J=1.7 and 10 Hz, 1H), 7.64 (q, J=8.8 and 14.4 Hz, 1H), 7.51 (t, J=7.6 Hz, 1H), 7.04 (t, J=8.4 Hz, 2H), 6.66 (s, 1H), 5.36 (s, 2H), 3.95 (s, 3H), 2.01 (s, 3H) ppm. 19F NMR (400 MHz, CD3OD) δ −111.50 (1F), −115.97 (1F), −123.01 (1F) ppm. ES-HRMS m/z 484.0169 (M+H calcd for C21H16BrF3NO4 requires 484.0192).
Reaction SMILES: CS(Cl)(=O)=O.[CH3:6][O:7][C:8]1[CH:24]=[C:23]2[C:11]([CH2:12][C:13]3[CH:17]=[C:16]([CH3:18])[N:15]([CH2:19][C@H:20](O)[CH3:21])[C:14]=32)=[CH:10][CH:9]=1.C(N(CC)CC)C.[N-:32]=[N+:33]=[N-:34].[Na+]>ClCCl.CN(C)C=O.O>[N:32]([C@@H:20]([CH3:21])[CH2:19][N:15]1[C:16]([CH3:18])=[CH:17][C:13]2[CH2:12][C:11]3[C:23]([C:14]1=2)=[CH:24][C:8]([O:7][CH3:6])=[CH:9][CH:10]=3)=[N+:33]=[N-:34]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc2c(c1)-c1c(cc(C)n1C[C@@H](C)O)C2
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)-c1c(cc(C)n1C[C@H](C)N=[N+]=[N-])C2
Yield: 50.1 %

Procedure:
0.48 ml of methanesulfonyl chloride was added dropwise while stirring to a solution, cooled to 0°, of 0.8 g of (R)-1-(7-methoxy-2-methyl-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol and 1.73 ml of triethylamine in 40 ml of dichloromethane and the mixture was stirred at this temperature for an additional 1.5 hours. The reaction mixture was subsequently diluted with 100 ml of dichloromethane, washed twice with 70 ml of saturated sodium hydrogen carbonate solution each time and the combined aqueous phases were extracted once with 60 ml of dichloromethane. The combined organic phases were washed with 70 ml of saturated sodium chloride solution, dried over magnesium sulfate and evaporated in a vacuum. The brown oil obtained was dissolved in 25 ml of anhydrous dimethylformamide, treated with 0.40 g of sodium azide and the reaction mixture was heated to 60° for 16 hours while stirring. After cooling, the solution was poured into 70 ml of water and extracted twice with 100 ml of ethyl acetate each time. The combined organic phases were washed once with 70 ml of water and once with 70 ml of saturated sodium chloride solution, dried over magnesium sulfate and the solution was concentrated in a vacuum. The brown oil obtained was purified by column chromatography on silica gel (toluene). 0.44 g (50%) of (S)-1-(2-azido-propyl)-7-methoxy-2-methyl-1,4-dihydro-indeno[1,2-b]pyrrole was obtained as a light yellow oil.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6](F)[N:5]=[CH:4][N:3]=1.[CH2:10]([OH:15])[C:11]#[C:12][CH2:13][CH3:14].C(N(CC)CC)C>C1(C)C=CC=CC=1>[F:1][C:2]1[C:7]([F:8])=[C:6]([O:15][CH2:10][C:11]#[C:12][CH2:13][CH3:14])[N:5]=[CH:4][N:3]=1
Reactant: CCC#CCO
Reactant: Fc1ncnc(F)c1F
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCC#CCOc1ncnc(F)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.7 %

Procedure:
0.5 g of 4,5,6-trifluoropyrimidine, 0.38 g of 2-pentyn-1-ol and 0.62 ml of triethylamine were added to 1 ml of toluene, then the mixture was stirred at room temperature for 1 hour. Then the reaction mixture was subjected to silica gel column chromatography to obtain 0.53 g of 4,5-difluoro-6-(2-pentynyloxy)pyrimidine.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[C@@H:7]([NH2:24])[CH2:8][NH:9][C:10](=[O:23])[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:33]([NH:36][C:37]1[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[CH:39][CH:38]=1)(=[O:35])[CH3:34]>CN(C)C=O>[C:1]([O:5][C:6](=[O:25])[C@@H:7]([NH:24][S:43]([C:40]1[CH:39]=[CH:38][C:37]([NH:36][C:33](=[O:35])[CH3:34])=[CH:42][CH:41]=1)(=[O:45])=[O:44])[CH2:8][NH:9][C:10](=[O:23])[C:11]1[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:15][CH:16]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)CCc1ccc(C(=O)NC[C@H](N)C(=O)OC(C)(C)C)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)CCc1ccc(C(=O)NC[C@H](NS(=O)(=O)c2ccc(NC(C)=O)cc2)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.123 g (0.35 mmol) of (2S)-2-amino-3-(4-(2-methoxycarbonyl-ethyl) -benzoylamino)-propionic acid tert-butyl ester was dissolved in 2 ml of dimethylformamide and treated with 0.196 ml (1.4 mmol) of triethylamine and 0.164 g (0.7 mmol) of 4-acetylamino-benzenesulfonyl chloride. The solution was stirred for 4 hours at room temperature. The solvent was removed in vacuo, the residue was dissolved in dichloromethane and the solution was washed three times with water. The organic phase was dried with sodium sulfate, filtered and the solvent was removed in vacuo. The residue was chromatographed on silica gel eluting with n-heptane/ethyl acetate (1/2). Yield 90 mg. MS (ES+): m/e=548 (M+H+).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10](=[O:12])[CH3:11])[C:5]([Cl:13])=[CH:4][N:3]=1.[OH:14]S(O)(=O)=O.[NH4+].[OH-]>O>[Cl:13][C:5]1[C:6]([CH2:8][NH:9][C:10](=[O:12])[CH3:11])=[CH:7][C:2](=[O:14])[NH:3][CH:4]=1
Reactant: CC(=O)NCc1cc(Cl)ncc1Cl
Reactant: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: CC(=O)NCc1cc(=O)[nH]cc1Cl
Temperature: 200 °C

Procedure:
Compound N-(2,5-dichloro-pyridin-4-ylmethyl)-acetamide (250 mg, 1.14 mmol) was added to 33% H2SO4 (3 mL) and the mixture heated in a CEM microwave reactor at 200° C. for 30 min. After cooling to room temperature, the reaction mixture was diluted with water (20 mL) and basified with excess concentrated NH4OH. The reaction mixture was then frozen using a dry ice/acetone bath and evaporated to dryness in vacuo overnight in a freeze-dry apparatus. The solids were purified by column chromatography using a 12 g ISCO combi-flash column and dry-loading cartridge (silica gel, 100:0 to 50:50 DCM:DCM/MeOH/NH4OH 6:3:1) to afford N-(5-chloro-2-oxo-1,2-dihydro-pyridin-4-ylmethyl)-acetamide (246 mg, quant.) as an off-white solid. This material was directly in the next step.