Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:21][CH:20]=1)[C:3]([NH:5][C:6]1[C:11]([CH:12]([CH3:14])[CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=1[CH:15]([CH3:17])[CH3:16])=[O:4].C(N(CC)CC)C.[CH3:40][O:41][C:42](Cl)=[O:43]>C1COCC1>[CH3:17][CH:15]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]([CH3:14])[CH3:13])[C:6]=1[NH:5][C:3](=[O:4])[C@@H:2]([NH:1][C:42](=[O:43])[O:41][CH3:40])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[CH:21][CH:20]=1)[CH3:16]
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)[C@@H](N)Cc1ccc(OCc2ccccc2)cc1
Reactant: COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)Nc1c(C(C)C)cccc1C(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 58.5 %

Procedure:
To a coded (0° C.) solution of (S)-α-amino-N-[2,6-bis(1-Methylethyl)phenyl]-4-(phenylmethoxy)benzenepropanamide (4.50 g, 10.5 mmol) and triethylamine (1.75 mL, 12.5 mmol) in THF (125 mL) was added methylchloroformate (0.97 mL, 12.5 mmol). The resulting slurry was stirred (1 hr, 0° C.) then filtered, and the filtrate was concentrated. The residue was taken up in ethyl acetate (300 mL), washed with water (1×mL), washed with saturated sodium bicarbonate (1×100 mL), washed with brine (1×100 mL), then dried (MgSO4) and concentrated in vacuo. The resulting solid was recrystallized from ethyl acetate to yield 3.0 g (59%) of the title compound, mp 179°-182° C.
Reaction SMILES: [CH3:1][C:2]([S@:5]([NH2:7])=[O:6])([CH3:4])[CH3:3].[Br:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]=O)=[N:13][CH:14]=1>C(Cl)Cl.[O-]S([O-])(=O)=O.[Cu+2]>[Br:8][C:9]1[CH:10]=[CH:11][C:12](/[CH:15]=[N:7]/[S@@:5]([C:2]([CH3:4])([CH3:3])[CH3:1])=[O:6])=[N:13][CH:14]=1
Reactant: O=Cc1ccc(Br)cn1
Reactant: CC(C)(C)[S@](N)=O
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: CC(C)(C)[S@@](=O)/N=C/c1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 21 h
Yield: 97.1 %

Procedure:
To a solution of (R)-(+)-2-methyl-2-propanesulfinamide (2.60 g, 21.5 mmol) in 100 mL of CH2Cl2 at room temperature was added CuSO4 (7.53 g, 47.2 mmol) and 5-bromo-pyridine-2-carbaldehyde (4.39 g, 23.6 mmol). The reaction mixture was stirred at room temperature for 21 h and then filtered through Diatomaceous earth, washing with CH2Cl2. The filtrates were concentrated to give a pale brown oil that was purified by flash chromatography on silica gel, eluting with 10-25% EtOAc in hexanes, to afford 6.04 g (97%) of (R)-2-methyl-propane-2-sulfinic acid 1-(5-bromo-pyridin-2-yl)-meth-(E)-ylideneamide as a pale yellow solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[CH:17][CH:16]=[CH:15]2)=[CH:10][C:9]=1[NH2:19])(C)(C)C.C(O[C:26](=[O:43])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:37]=[N:38][C:39]([CH3:42])=[CH:40][CH:41]=2)[CH:31]=1)=O)(C)(C)C>>[CH3:42][C:39]1[N:38]=[CH:37][C:36]([C:32]2[CH:31]=[C:30]([C:28]3[CH2:27][C:26](=[O:43])[NH:19][C:9]4[CH:10]=[C:11]([N:14]5[CH:18]=[CH:17][CH:16]=[CH:15]5)[CH:12]=[CH:13][C:8]=4[N:7]=3)[CH:35]=[CH:34][CH:33]=2)=[CH:41][CH:40]=1
Reactant: Cc1ccc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cn1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-n2cccc2)cc1N
Product: Cc1ccc(-c2cccc(C3=Nc4ccc(-n5cccc5)cc4NC(=O)C3)c2)cn1

Procedure:
The title compound was prepared from (2-amino-4-pyrrol-1-yl-phenyl)-carbamic acid tert-butyl ester (Example J11) (273 mg, 1 mmol) and 3-[3-(6-methyl-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K4) (311 mg, 1 mmol) according to the general procedure M and subsequent treatment of the crude product according to the general procedure N. Obtained as a yellow solid (195 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:20])[CH:5]=[C:6]([Cl:19])[C:7]=1[CH2:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[Cl:21][C:22]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=1[S:32](Cl)(=[O:34])=[O:33]>N1C=CC=CC=1>[Cl:21][C:22]1[CH:27]=[C:26]([C:28]([F:30])([F:29])[F:31])[CH:25]=[CH:24][C:23]=1[S:32]([NH:20][C:4]1[CH:5]=[C:6]([Cl:19])[C:7]([CH2:8][C:9]2[CH:10]=[N:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:2]([Cl:1])[CH:3]=1)(=[O:34])=[O:33]
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1Cl
Reactant: Nc1cc(Cl)c(Cc2cnc3ccccc3c2)c(Cl)c1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cc(Cl)c(Cc2cnc3ccccc3c2)c(Cl)c1)c1ccc(C(F)(F)F)cc1Cl

Procedure:
2-Chloro-N-(3,5-dichloro-4-quinolin-3-ylmethyl-phenyl)-4-trifluoromethyl-benzenesulfonamide was synthesized (80%) from 3,5-dichloro-4-quinolin-3-ylmethyl-phenylamine (230), 2-chloro-4-trifluoromethylbenzenesulfonyl chloride (Maybridge) and pyridine (EM) in a similar manner as described in Examples 70-91. 1H NMR (400 MHz, DMSO-d6) δ 11.49 (br s, 1H), 8.78 (d, J=1.9 Hz, 1H), 8.34 (d, J=8.3 Hz, 1H), 8.19 (s, 1H), 7.98 (d, J=7.0 Hz, 1H), 7.96 (d, J=7.7 Hz, 1H), 7.86 (d, J=8.0 Hz, 1H), 781 (s, 1H), 7.70 (t, J=7.6 Hz, 1H), 7.23 (t, J=7.5 Hz, 1H), 7.24 (s, 2H), 4.34 (s, 2H). MS (EI): m/z 543 (M−H).
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[NH:13][C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=1)SC)#[N:2].[CH2:21]([NH2:23])[CH3:22]>>[N:16]1[C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[NH:13][C:12]=1[CH2:11][S:10][CH2:9][CH2:8][NH:7][C:4]([NH:3][C:1]#[N:2])=[N:23][CH2:21][CH3:22]
Reactant: CSC(=NCCSCc1nc2ccccc2[nH]1)NC#N
Reactant: CCN
Product: CCN=C(NC#N)NCCSCc1nc2ccccc2[nH]1

Procedure:
Reacting N-cyano-N'-[2-(2-benzimidazolylmethylthio)ethyl]-S-methylisothiourea with ethylamine by the procedure of Example 4 gives N-[2-(2-benzimidazolylmethylthio)ethyl-N'-cyano-N"-ethylguanidine.
Reaction SMILES: C(=O)(O)[O-].[Na+].[Cl:6][C:7]1[N:12]=[C:11](Cl)[CH:10]=[CH:9][N:8]=1.[CH3:14][O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1>C(O)C.O>[Cl:6][C:7]1[N:12]=[C:11]([NH:20][C:19]2[CH:21]=[CH:22][C:16]([O:15][CH3:14])=[CH:17][CH:18]=2)[CH:10]=[CH:9][N:8]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: COc1ccc(N)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc(Nc2ccnc(Cl)n2)cc1
Temperature: 0 °C
Reaction time: 6 h
Yield: 75.1 %

Procedure:
Sodium bicarbonate (1.26 g, 11.9 mmol) is added to a slurry of 2,4-dichloropyrimidine (1.01 g, 6.78 mmol) in ethanol (30 mL) at 0° C. 4-Methoxyaniline (840 mg, 6.82 mmol) is added and the slurry stirred at 0° C. for 6 hours. The reaction mixture is warmed to room temperature for 1 hour, then diluted with water (50 mL) and extracted three times with CHCl3 (50 mL). The combined organic layers are washed with water (50 mL) and brine (50 mL), dried over sodium sulfate, filtered and concentrated in vacuo to give crude product which is purified over silica (10% Et2O/CH2Cl2) to afford 1.20 g (75% yield) of the desired product as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.05 (d, J=5.8 Hz, 1H), 7.20 (d, J=9.0 Hz, 2H), 7.05 (br s, 1H), 6.94 (d, J=9.0 Hz, 2H), 6.41 (d, J=5.8 Hz, 1H), 3.83 (s, 3H); MS (ESI) m/z 236 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.CN(C)P(N(C)C)(N(C)C)=O.Br[CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O>[O:27]([CH2:26][CH2:25][NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: BrCCOc1ccccc1
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CCOC(=O)c1ccc(NCCOc2ccccc2)cc1
Temperature: 110 °C

Procedure:
A mixture of 33 g of ethyl p-aminobenzoate, 80 ml of hexamethylphosphoramide and 20.1 g of β-bromophenetole is heated at 110° C. for 20 hours. The mixture is cooled, diluted with 25 ml of water, chilled, filtered and the solid washed with ethanol and with water to give crystals, mp 126°-129° C. Recrystallization from ethanol gives pale yellow crystals, mp 129°-131° C.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:29][C:30]1[CH:39]=[CH:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=1)[C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][C@H:10]([N:13]([S:18]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[C:23]([NH2:28])[CH:22]=1)(=[O:20])=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:11][OH:12])=[O:4].[C:40](Cl)(=[O:42])[CH3:41]>>[C:40]([NH:1][C@@H:2]([CH2:29][C:30]1[CH:39]=[CH:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=1)[C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][C@H:10]([N:13]([S:18]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[C:23]([NH2:28])[CH:22]=1)(=[O:19])=[O:20])[CH2:14][CH:15]([CH3:16])[CH3:17])[CH2:11][OH:12])=[O:4])(=[O:42])[CH3:41]
Reactant: CC(=O)Cl
Reactant: CC(C)CN([C@H](CO)CCCCNC(=O)[C@@H](N)Cc1ccc2ccccc2c1)S(=O)(=O)c1ccc(F)c(N)c1
Product: CC(=O)N[C@@H](Cc1ccc2ccccc2c1)C(=O)NCCCC[C@@H](CO)N(CC(C)C)S(=O)(=O)c1ccc(F)c(N)c1

Procedure:
The title compound was prepared from (2S,5S)-2-amino-N-{5-[(3-amino-4-fluoro-benzenesulfonyl)-isobutyl-amino]-6-hydroxy-hexyl}-3-naphthalen-2-yl-propionamide (example 81) as described in general procedure D using acetyl chloride. The final product was obtained in 26% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:27])[C:10]([C:16]1[CH:17]=[CH:18][C:19]2[O:23][C:22](=[O:24])[N:21]([CH3:25])[C:20]=2[CH:26]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[CH3:28][O:29][C:30](=[O:39])[C:31]1[CH:36]=[C:35]([Cl:37])[C:34](Cl)=[N:33][CH:32]=1>>[CH3:28][O:29][C:30](=[O:39])[C:31]1[CH:36]=[C:35]([Cl:37])[C:34]([O:8][C:6]2[CH:5]=[CH:4][C:3]([CH:9]([CH3:27])[C:10]([OH:15])([C:16]3[CH:17]=[CH:18][C:19]4[O:23][C:22](=[O:24])[N:21]([CH3:25])[C:20]=4[CH:26]=3)[C:11]([F:12])([F:13])[F:14])=[C:2]([Cl:1])[CH:7]=2)=[N:33][CH:32]=1
Reactant: COC(=O)c1cnc(Cl)c(Cl)c1
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccc2oc(=O)n(C)c2c1)C(F)(F)F
Product: COC(=O)c1cnc(Oc2ccc(C(C)C(O)(c3ccc4oc(=O)n(C)c4c3)C(F)(F)F)c(Cl)c2)c(Cl)c1

Procedure:
The title compound was prepared in analogy to Example 174 from 5-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-3-methyl-3H-benzooxazol-2-one (obtained in Example 172) with methyl-5,6-dichloronicotinate [CAS Reg. No. 56055-54-0]. MS (m/e)=571.2 [M+H+].
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]1[CH2:24][C@:11]2([O:15][C:14](=[O:16])[N:13]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=3)[CH2:12]2)[CH2:10][NH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:25]1([CH2:31][C:32]([NH:34][C@@H:35]([C:39]([CH3:42])([CH3:41])[CH3:40])[C:36](O)=[O:37])=[O:33])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[C:1]([O:5][C:6]([C@@H:8]1[CH2:24][C@:11]2([O:15][C:14](=[O:16])[N:13]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=3)[CH2:12]2)[CH2:10][N:9]1[C:36](=[O:37])[C@@H:35]([NH:34][C:32](=[O:33])[CH2:31][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)[C:39]([CH3:41])([CH3:42])[CH3:40])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[C@H](NC(=O)CC1CCCCC1)C(=O)O
Reactant: CC(C)(C)OC(=O)[C@@H]1C[C@]2(CN1)CN(c1cccc(Cl)c1)C(=O)O2
Product: CC(C)(C)OC(=O)[C@@H]1C[C@@]2(CN(c3cccc(Cl)c3)C(=O)O2)CN1C(=O)[C@@H](NC(=O)CC1CCCCC1)C(C)(C)C
Yield: 46.2 %

Procedure:
Following the procedure from Example 1 step G using (5S,8S)-tert-butyl-3-(3-chlorophenyl)-2-oxo-1-oxa-3,7-diazaspiro[4.4]nonane-8-carboxylate (B5) (32 mg, 91 μmol, 1 eq.) and (5)-2-(2-cyclohexylacetamido)-3,3-dimethylbutanoic acid (25 mg, 100 μmol, 1.2 eq.) gave 25 mg (42 μmol) of (5S,8S)-tert-butyl-3-(3-chlorophenyl)-7-((S)-2-(2-cyclohexylacetamido)-3,3-dimethylbutanoyl)-2-oxo-1-oxa-3,7-diazaspiro[4.4]nonane-8-carboxylate (C5). LC MS+/−: 590.31/589.47 at 3.95 min (10-90%, 3-5 min, Formic Acid).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13](=O)[NH:14][CH:15]=[N:16]3)=[CH:11][C:10]=2[O:20][CH3:21])[CH:5]=[CH:4][N:3]=[CH:2]1.S(Cl)([Cl:24])=O>>[Cl:24][C:13]1[C:12]2[C:17](=[CH:18][C:9]([O:8][CH2:7][CH2:6][N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)=[C:10]([O:20][CH3:21])[CH:11]=2)[N:16]=[CH:15][N:14]=1
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCCn1ccnc1
Reactant: O=S(Cl)Cl
Product: COc1cc2c(Cl)ncnc2cc1OCCn1ccnc1

Procedure:
Using a procedure analogous to the one described for the synthesis of Example 23, 7-(2-(imidazol-1-yl)ethoxy)-6-methoxy-3,4-dihydroquinazoline-4-one (286 mg, 1 mmol) was reacted with thionyl chloride (50 ml) to give 4-chloro-7-(2-(imidazol-1-yl)ethoxy)-6-methoxyquinazoline which was then reacted with 5,7-diaza-6-methyloxindole (440 mg, 3 mmol) and sodium hydride (120 mg, 3 mmol) to give 4-(5,7-diaza-6-methyloxindol-3-yl)-7-(2-(imidazol-1-yl)ethoxy)-6-methoxyquinazoline hydrochloride (80 mg, 15%).
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]3[CH2:17][CH2:16][C:15]4[C:7]3=[C:8]([CH:12]=[CH:13][CH:14]=4)[C:9](=O)[NH:10][C:4]=2[CH:3]=1.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.[OH-].[Na+]>[Ti](Cl)(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]3[CH2:17][CH2:16][C:15]4[C:7]3=[C:8]([CH:12]=[CH:13][CH:14]=4)[C:9]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[N:10][C:4]=2[CH:3]=1
Reactant: C1COCCN1
Reactant: O=C1Nc2cc(Br)ccc2N2CCc3cccc1c32
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Brc1ccc2c(c1)N=C(N1CCOCC1)c1cccc3c1N2CC3
Temperature: 25 °C

Procedure:
A mixture of 7.88 g (0.0250 mole) of 9-bromo-1,2-dihydrobenzo[b]pyrrolo[3,2,1-jk][1,4]benzodiazepin-6-one and 1200 ml of toluene was heated under nitrogen, with stirring, until a solution resulted. Then there was added 21.8 g (0.250 mole) of morpholine, followed by 14.2 g (0.075 mole) of titanium tetrachloride. The mixture was heated under reflux for three hours, cooled to room temperature and treated with 500 ml of 2N sodium hydroxide solution. After stirring vigorously for 15 minutes, the layers were separated. The aqueous phase was extracted with 250 ml of toluene. The toluene layers were combined, washed once with 2N sodium hydroxide solution, twice with water, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to 8.6 g (90%) of product. Recrystallization from a hot solution of dichloromethane (80 ml) to which methanol (80 ml) was added provided the analytical sample, mp 216°-218° C.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[C@H:4]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH3:5].[F:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][NH2:24])=[CH:17][CH:16]=1.FC(F)(F)S([O-])(=O)=O.[Li+]>C(#N)C>[C:9]([O:8][C:7](=[O:13])[NH:6][C@H:4]([CH3:5])[C@@H:2]([OH:1])[CH2:3][NH:24][CH2:23][CH2:22][CH2:21][C:18]1[CH:17]=[CH:16][C:15]([F:14])=[CH:20][CH:19]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1CO1
Reactant: NCCCc1ccc(F)cc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Li+]
Solvent: CC#N
Product: C[C@@H](NC(=O)OC(C)(C)C)[C@@H](O)CNCCCc1ccc(F)cc1
Reaction time: 8 h
Yield: 80.3 %

Procedure:
The product from step c (823 mg, 4.39 mMol) and 3-(4-fluorophenyl)propylamine (674 mg, 4.39 mMol) were dissolved in anhydrous acetonitrile (10 ml). To this solution, lithium trifluoromethanesulfonate (1.44 g, 9.23 mMol) was added, and the solution was stirred overnight. The mixture was concentrated in-vacuo, then the residue was dissolved in EtOAc (60 ml), washed with saturated sodium bicarbonate (2×20 ml), followed by water (20 ml). The organic phase was dried over sodium sulfate and concentrated to a yellow oil. Purified via flash chromatography, eluting with EtOAc, 2.5% 7N NH4 in MeOH/EtOAc, 5% 7N NH4 in MeOH/EtOAc to yield 1.2 g of a colorless oil as product. ESI+MS detects 341 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]3[N:15]([CH3:19])[C:16](=[O:18])[NH:17][C:13]=3[CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Cl)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[C:14]3[N:15]([CH3:19])[C:16](=[O:18])[N:17]([CH2:26][C:25]4[CH:28]=[CH:29][C:22]([O:21][CH3:20])=[CH:23][CH:24]=4)[C:13]=3[CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: Cn1c(=O)[nH]c2cccc(Nc3ccc(Cl)cc3)c21
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Cn2c(=O)n(C)c3c(Nc4ccc(Cl)cc4)cccc32)cc1
Temperature: 70 °C
Reaction time: 1.67 h

Procedure:
A mixture of 7-[(4-chlorophenyl)amino]-1-methyl-1,3-dihydro-2H-benzimidazol-2-one (0.27 g, 1.0 mmol), 4-methoxybenzyl chloride (0.17 ml, 1.20 mmol), potassium carbonate (0.21 g, 1.50 mmol) and N,N-dimethylformamide (1 ml) was stirred at 70° C. for 100 min. The mixture was diluted with water (20 ml) and extracted with ethyl acetate (30 ml). The extract was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was flash chromatographed eluting with a 15% ethyl acetate/hexanes to give 0.39 g (quant.) of the title compound as a powder.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([OH:40])[CH2:11][S:12][C@H:13]3[C:16](=[O:17])[N:15]([C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=4)[C@@H:14]3[C:25]3[CH:39]=[CH:38][C:28]([O:29][CH2:30][C:31]([NH:33][CH2:34][C:35](O)=[O:36])=[O:32])=[CH:27][CH:26]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:70][C@@H:71]([C:75]([OH:77])=[O:76])[CH:72]([CH3:74])[CH3:73]>CN(C=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([OH:40])[CH2:11][S:12][C@H:13]3[C:16](=[O:17])[N:15]([C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=4)[C@@H:14]3[C:25]3[CH:39]=[CH:38][C:28]([O:29][CH2:30][C:31]([NH:33][CH2:34][C:35]([NH:70][C@@H:71]([C:75]([OH:77])=[O:76])[CH:72]([CH3:74])[CH3:73])=[O:36])=[O:32])=[CH:27][CH:26]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)[C@@H](N)C(=O)O
Reactant: O=C(O)CNC(=O)COc1ccc([C@@H]2[C@@H](SCC(O)c3ccc4c(c3)OCO4)C(=O)N2c2ccc(F)cc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)[C@@H](NC(=O)CNC(=O)COc1ccc([C@@H]2[C@@H](SCC(O)c3ccc4c(c3)OCO4)C(=O)N2c2ccc(F)cc2)cc1)C(=O)O
Temperature: 30 °C
Reaction time: 1 h

Procedure:
To a stirred solution of N-({4-[(2R,3R)-3-{[2-(1,3-benzodioxol-5-yl)-2-hydroxyethyl]thio}-1-(4-fluorophenyl)-4-oxoazetidin-2-yl]phenoxy}acetyl)glycine (12.8 mg, 0.023 mmol) in DMF (2 ml) was added N-methylmorpholine (15 μl, 0.091 mmol). TBTU (8.8 mg, 0.027 mmol) was added and the reaction mixture was stirred at 30° C. for 1 hour. D-valine (4.5 mg, 0.038 mmol) was added and the mixture was stirred at ambient temperature overnight. The solution was purified with preparative HPLC on a C8 column, UV 240/260 nm. A gradient from 20 to 45% MeCN in 0.1M NH4OAc buffer was used as eluent. The pure fractions were collected and the MeCN was removed under reduced pressure. The remaining water solution was acidified to pH 1 with HCl (1M) and extracted with DCM. The organic phase was passed through a phase separator and concentrated under reduced pressure. The residue was dissolved in MeCN and water. After lyophilisation, the title compound was obtained. H-NMR (400 MHz, DMSO-d6): 0.80 (bs, 6H), 1.92-2.04 (m, 1H), 2.77-2.90 (m, 2H), 3.77 (bs, 2H), 3.94-4.10 (b, 1H), 4.22-4.30 (m, 1H), 4.49 (s, 2H), 4.56-4.64 (m, 1H), 4.99-5.03 (m, 1H), 5.90-5.94 (m, 2H), 6.70-6.79 (m, 2H), 6.82 (s, 1H), 6.96 (d, 2H), 7.09-7.15 (m, 2H), 7.18-7.24 (m, 2H), 7.34 (d, 2H), 8.23 (bs, 1H). M/z: 666.67 (M−1).
Reaction SMILES: [F:1][C:2]1[C:7](F)=[CH:6][C:5]([NH2:9])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:19]([SH:22])[CH2:20][CH3:21]>CN(C=O)C>[F:1][C:2]1[C:7]([S:22][CH2:19][CH2:20][CH3:21])=[CH:6][C:5]([NH2:9])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1
Reactant: Nc1cc(F)c(F)cc1[N+](=O)[O-]
Reactant: CCCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCSc1cc(N)c([N+](=O)[O-])cc1F
Temperature: 90 °C
Yield: 98.7 %

Procedure:
To a mixture of 4,5-difluoro-2-nitro-phenylamine (1.51 g, 8.67 mmol), potassium carbonate (2.40 g, 17.3 mmol), and DMF (43 mL) was added 1-propanethiol (0.865 mL, 9.54 mmol). The reaction mixture was heated at 90° C. for 1.5 h, and allowed to cool to 23° C. The mixture was poured into ice/brine (400 mL) and the resulting precipitate was collected to yield the titled compound (1.97 g, 98% yield). MS (ESI/CI): mass calcd. for C9H11FN2O2S, 230.1; m/z found, 231.1 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.78 (d, J=10.3 Hz, 1H), 6.52 (d, J=6.3 Hz, 1H), 6.04 (s, 2H), 2.93 (t, J=7.3 Hz, 2H), 1.84-1.70 (m, 2H), 1.09 (t, J=7.4 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]2[C:9]([C:17]3[S:18][C:19]([Cl:22])=[CH:20][CH:21]=3)=[N:10][N:11]([CH:13]([CH2:15][CH3:16])[CH3:14])[CH:12]=2)[CH:5]=[CH:4][N:3]=1.[CH:23]1([C:26]#[CH:27])[CH2:25][CH2:24]1.C(N(CC)C(C)C)(C)C>O1CCCC1.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:13]([N:11]1[CH:12]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:27]#[C:26][CH:23]3[CH2:25][CH2:24]3)[CH:7]=2)[C:9]([C:17]2[S:18][C:19]([Cl:22])=[CH:20][CH:21]=2)=[N:10]1)([CH2:15][CH3:16])[CH3:14]
Reactant: CCC(C)n1cc(-c2ccnc(Br)c2)c(-c2ccc(Cl)s2)n1
Reactant: C#CC1CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCC(C)n1cc(-c2ccnc(C#CC3CC3)c2)c(-c2ccc(Cl)s2)n1
Temperature: 120 °C
Reaction time: 0.05 h
Yield: 50.9 %

Procedure:
To a solution of 2-bromo-4-[1-sec-butyl-3-(5-chloro-2-thienyl)-1H-pyrazol-4-yl]pyridine (0.18 mmol) in 2 mL of tetrahydrofurane was added cyclopropylacetylene (0.71 mmol), copper iodide (0.053 mmol), dichlorobis(triphenylphosphine)palladium (II) (0.053 mmol) and N,N-diisopropylethlamine (0.88 mmol). The resulting mixture was stirred in the microwave at 120° C. for 3 min. The solvent was then evaporated and the residue was purified by chromatography on silica gel (hepthane:ethyl acetate 5:1 to 2:1) to afford 35 mg of 4-[1-sec-butyl-3-(5-chloro-2-thienyl)-1H-pyrazol-4-yl]-2-(cyclopropylethynyl)pyridine (51% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=2)[N:12]=[CH:11][N:10]=1>C(O)(C)C>[C:2]1([NH:1][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: O=[N+]([O-])c1ccc2ncnc(Cl)c2c1
Solvent: CC(C)O
Product: O=[N+]([O-])c1ccc2ncnc(Nc3ccccc3)c2c1

Procedure:
Aniline or derivatized aniline (1 equivalent) is reacted with 4-chloro-6-nitroquinazoline (3.5 equivalents), in a polar solvent such as iso-propylalcohol. The product, 4-(phenylamino)-6-nitroquinazoline, is obtained after filtration.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:54])[C@@H:4]([NH:21][C:22]([C@@H:24]1[CH2:33][C:32]2[CH:31]=[C:30]3[O:34][CH2:35][C@H:36]([C:38]4[CH:43]=[CH:42][C:41]([O:44][CH2:45][C:46]5[CH:51]=[CH:50][C:49]([Cl:52])=[C:48]([Cl:53])[CH:47]=5)=[CH:40][CH:39]=4)[O:37][C:29]3=[CH:28][C:27]=2[CH2:26][NH:25]1)=[O:23])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][N:16]=[C:15]([CH3:19])[C:14]=2[CH3:20])=[CH:8][CH:7]=1.[N:55]([C@H:58]([C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[CH3:59])=[C:56]=[O:57]>>[CH3:1][O:2][C:3](=[O:54])[C@@H:4]([NH:21][C:22]([C@@H:24]1[CH2:33][C:32]2[CH:31]=[C:30]3[O:34][CH2:35][C@H:36]([C:38]4[CH:43]=[CH:42][C:41]([O:44][CH2:45][C:46]5[CH:51]=[CH:50][C:49]([Cl:52])=[C:48]([Cl:53])[CH:47]=5)=[CH:40][CH:39]=4)[O:37][C:29]3=[CH:28][C:27]=2[CH2:26][N:25]1[C:56](=[O:57])[NH:55][C@H:58]([C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[CH3:59])=[O:23])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][C:13]2[CH:18]=[CH:17][N:16]=[C:15]([CH3:19])[C:14]=2[CH3:20])=[CH:10][CH:11]=1
Reactant: C[C@H](N=C=O)c1ccccc1
Reactant: COC(=O)[C@H](Cc1ccc(Oc2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Product: COC(=O)[C@H](Cc1ccc(Oc2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1C(=O)N[C@@H](C)c1ccccc1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3

Procedure:
(S)-2-({(3S,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-[4-(2,3-dimethyl-pyridin-4-yloxy)-phenyl]-propionic acid methyl ester was reacted with (S)-1-isocyanato-ethyl-benzene according to General Procedure I to give (S)-2-{[(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-ethylcarbamoyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yloxy)-phenyl]-propionic acid methyl ester. This ester was hydrolyzed according to General Procedure B to give the title compound (15 mg). LCMS (m/z): 902.