Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:25][C:26]1[C:30]([Cl:31])=[C:29]([CH3:32])[NH:28][C:27]=1[C:33]([NH:35][C@H:36]1[CH2:41][CH2:40][N:39]([C:42]2[CH:50]=[C:49]([C:51]([O:53][CH2:54][CH3:55])=[O:52])[C:45]([C:46]([OH:48])=O)=[CH:44][N:43]=2)[CH2:38][C@H:37]1[O:56][CH3:57])=[O:34].CCN(CC)CC.[C:65]([NH2:74])([C:68]1[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=1)([CH3:67])[CH3:66]>CN(C=O)C.O>[Cl:25][C:26]1[C:30]([Cl:31])=[C:29]([CH3:32])[NH:28][C:27]=1[C:33]([NH:35][C@H:36]1[CH2:41][CH2:40][N:39]([C:42]2[CH:50]=[C:49]([C:45]([C:46]([NH:74][C:65]([CH3:67])([C:68]3[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=3)[CH3:66])=[O:48])=[CH:44][N:43]=2)[C:51]([O:53][CH2:54][CH3:55])=[O:52])[CH2:38][C@H:37]1[O:56][CH3:57])=[O:34]
Reactant: CCOC(=O)c1cc(N2CC[C@H](NC(=O)c3[nH]c(C)c(Cl)c3Cl)[C@H](OC)C2)ncc1C(=O)O
Reactant: CC(C)(N)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc(N2CC[C@H](NC(=O)c3[nH]c(C)c(Cl)c3Cl)[C@H](OC)C2)ncc1C(=O)NC(C)(C)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.6 %

Procedure:
HATU (87 mg, 24 mmol) was added to a solution of 118 mg (0.24 mmol) Cis(±)-6-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-4-(ethoxycarbonyl)nicotinic acid (Example 197), 0.040 ml (28 mmol) Et3N and 33 mg (0.24 mmol) cumylamine in 3 ml DMF. After stirring at room temperature overnight, the mixture was diluted with water and extracted with EtOAc. The EtOAc was washed 2 times with water and once with brine before being dried (MgSO4) and concentrated to give 103 mg of a solid. MS (ES) MH+: 616 for C30H35Cl2N5O5.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[S:13][C:14]([CH2:18]O)=[C:15]([CH3:17])[N:16]=2)=[CH:8][CH:7]=1.[NH:20]1[CH2:24][CH2:23][CH2:22][C:21]1=[O:25].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[S:13][C:14]([CH2:18][N:20]3[CH2:24][CH2:23][CH2:22][C:21]3=[O:25])=[C:15]([CH3:17])[N:16]=2)=[CH:10][CH:11]=1
Reactant: O=C1CCCN1
Reactant: Cc1nc(-c2ccc(OCCCCl)cc2)sc1CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1nc(-c2ccc(OCCCCl)cc2)sc1CN1CCCC1=O
Yield: 100 %

Procedure:
In a flask fitted with a magnetic stirrer and a reflux condenser, {2-[4-(3-chloropropoxy)phenyl]-4-methyl-1,3-thiazol-5-yl}methanol i109 (0.67 mmol, 1 eq, 0.2 g), pyrrolidinone (0.8 mmol, 1.2 eq, 0.069 g) and p-toluenesulfonic acid (0.067 mmol, 0.1 eq, 0.013 g) are dissolved in toluene (5 ml) and the mixture is brought to reflux overnight. After this time, the mixture is concentrated, taken up in ethyl acetate and washed with a saturated solution of sodium bicarbonate. The organic layer is dried over magnesium sulfate and concentrated to dryness to give 0.295 g of 1-({2-[4-(3-chloropropoxy)phenyl]-4-methyl-1,3-thiazol-5-yl}methyl)pyrrolidin-2-one i110. This crude product is used in the next step without further purification.
Reaction SMILES: [Na].[CH:2]([OH:5])(O)[CH3:3].Cl[C:7]1[N:11]([CH3:12])[C:10]2[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=2[N:8]=1.[OH2:17]>>[CH3:12][N:11]1[C:10]2[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=2[N:8]=[C:7]1[O:17][CH2:3][CH2:2][OH:5]
Reactant: Cn1c(Cl)nc2ccccc21
Reactant: CC(O)O
Reactant: O
Agent: [Na]
Product: Cn1c(OCCO)nc2ccccc21
Temperature: 60 °C
Reaction time: 3 h

Procedure:
Under an argon atmosphere, metal sodium (635 mg) was added to anhydrous ethanediol (12 mL), and the mixture was stirred at 60° C. for 3 hr. Then, 2-chloro-1-methyl-1H-benzimidazole (4.0 g) was added and the mixture was stirred with heating at 90° C. for 5 hr. The mixture was allowed to cool to room temperature, diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (3.0 g).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[N:11]=[C:12]=S)[CH3:2].[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([NH:23][C:24]([C:26]3[CH:43]=[CH:42][C:29]4[N:30]=C(NC5N(C(C)C)C=CN=5)[NH:32][C:28]=4[CH:27]=3)=[O:25])[CH:21]=2)[CH:16]=[N:15]1>CN(C=O)C.C1COCC1>[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([NH:23][C:24]([C:26]3[CH:43]=[CH:42][C:29]4[N:30]=[C:12]([NH:11][C:4]5[C:3]([CH2:1][CH3:2])=[CH:8][CH:7]=[CH:6][C:5]=5[CH2:9][CH3:10])[NH:32][C:28]=4[CH:27]=3)=[O:25])[CH:21]=2)[CH:16]=[N:15]1
Reactant: CCc1cccc(CC)c1N=C=S
Reactant: CC(C)n1ccnc1Nc1nc2ccc(C(=O)Nc3ccc4cn[nH]c4c3)cc2[nH]1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCc1cccc(CC)c1Nc1nc2ccc(C(=O)Nc3ccc4cn[nH]c4c3)cc2[nH]1

Procedure:
A solution of 1,3-diethyl-2-isothiocyanatobenzene (0.5 mmol) in 1:1 DMF/THF (2 mL) was reacted with 3,4-diamino-N-(1H-indazol-6-yl)-benzamide (0.5 mmol; see Example 25) according to general procedure B to yield 2-(2,6-diethylphenylamino)-3H-benzimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide. MS: m/z 425 (M+H)+.
Reaction SMILES: [Cl:1][CH2:2][C:3](OCC)(OCC)OCC.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[SH:20]>C(Cl)Cl>[Cl:1][CH2:2][C:3]1[S:20][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=1
Reactant: CCOC(CCl)(OCC)OCC
Reactant: Nc1ccccc1S
Solvent: ClCCl
Product: ClCc1nc2ccccc2s1
Temperature: 25 °C
Yield: 91.3 %

Procedure:
A solution of 2-chloro-1,1,1-triethoxyethane (5.9 g) and 2-aminothiophenol (2.5 g) was heated at 80° C. for 15 minutes. After cooling to room temperature, it was dissovled in methylene chloride (30 ml) and the resulting solution was washed with 3N HCl (10 ml) and then with water (20 ml). The organic portion was evaporated and the residue chromatographed over silica gel to obtain 2-chloromethylbenzothiazole (3.35 g; 90% yield), m.p. 34° C.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:17]([OH:19])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][O:13]2)[CH2:3][CH2:2]1.Cl.[NH2:21][C@@H:22]([CH2:27][CH:28]([CH3:30])[CH3:29])[C:23]([NH:25][CH3:26])=[O:24]>>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:17]([NH:21][C@@H:22]([CH2:27][CH:28]([CH3:30])[CH3:29])[C:23]([NH:25][CH3:26])=[O:24])=[O:19])=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][O:13]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CCCO2)n1
Reactant: CNC(=O)[C@@H](N)CC(C)C
Agent: Cl
Product: CNC(=O)[C@H](CC(C)C)NC(=O)c1ccc(C2CC2)c(OCC2CCCO2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2-carboxylic acid (Example 166 b) and (2S)-2-amino-N,4-dimethyl-pentanamide monohydrochloride (CAN 99145-71-8) as starting materials, MS (EI): m/e=390.0 [M+H]+.
Reaction SMILES: [N:1]([C:4]1[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8]C)=O)=[C:2]=[S:3].[NH2:14][CH2:15][CH:16]([N:18]1[CH2:23][CH2:22][CH:21]([C:24]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[O:25])[CH2:20][CH2:19]1)[CH3:17]>O1CCCC1>[F:32][C:29]1[CH:28]=[CH:27][C:26]([C:24]([CH:21]2[CH2:20][CH2:19][N:18]([CH:16]([CH3:17])[CH2:15][N:14]3[C:6](=[O:8])[C:5]4[C:4](=[CH:13][CH:12]=[CH:11][CH:10]=4)[NH:1][C:2]3=[S:3])[CH2:23][CH2:22]2)=[O:25])=[CH:31][CH:30]=1
Reactant: COC(=O)c1ccccc1N=C=S
Reactant: CC(CN)N1CCC(C(=O)c2ccc(F)cc2)CC1
Solvent: C1CCOC1
Product: CC(Cn1c(=S)[nH]c2ccccc2c1=O)N1CCC(C(=O)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 13 %

Procedure:
A mixture of 6.7 parts of methyl 2-isothiocyanatobenzoate, 8 parts of [1-(2-amino-1-methylethyl)-4-piperidinyl](4-fluorophenyl)methanone and 108 parts of tetrahydrofuran is stirred overnight at room temperature. The reaction mixture is evaporated. The residue is purified twice by column-chromatography over silica gel using first a mixture of trichloromethane and methanol (90:10 by volume) and then a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized twice from 2-propanol, yielding 1.6 parts (13%) of 3-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]propyl]-2,3-dihydro-2-thioxo-4(1H)-quinazolinone; mp. 160.6° C.
Reaction SMILES: [C:1]1([NH2:8])[C:2]([NH2:7])=[CH:3][CH:4]=[CH:5][CH:6]=1.[CH3:9][O:10][C:11]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:12]=1[CH:13]=O.C(O)(=O)C>C(O)C>[CH3:9][O:10][C:11]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:12]=1[C:13]1[NH:8][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=2[N:7]=1
Reactant: Nc1ccccc1N
Reactant: COc1ccc(C=O)c(OC)c1
Solvent: CCO
Solvent: CC(=O)O
Product: COc1ccc(-c2nc3ccccc3[nH]2)c(OC)c1
Yield: 12.4 %

Procedure:
Ex-70A: A solution of benzene-1,2-diamine (2.60 g, 24.1 mmol) and 2,4-dimethoxy-benzaldehyde (4.0 g, 24.1 mmol) in ethanol (60 mL) containing catalytic amount of acetic acid was refluxed overnight. Solvent was then evaporated under reduced pressure. The residue oil was triturated in ethyl acetate to obtain 2-(2,4-dimethoxy-phenyl)-1H-benzoimidazole (0.76 g, 12%). The crude product was used without further purification. To a solution of 2-(2,4-dimethoxy-phenyl)-1H-benzoimidazole obtained above (0.76 g, 2.99 mmol) in dichloromethane (20 mL) was added dichloromethyl methyl ether (0.41 mL, 4.48 mmol) followed by addition of titanium tetrachloride (1.0M in dichloromethane, 9.0 mL, 9.0 mmol) at 0° C. The reaction mixture was allowed to stir overnight at ambient temperature and then poured into ice. A solution of sodium hydroxide (5M) was added dropwise until the pH of the solution was about 12. The basic solution was extracted with dichloromethane. The combined solution of dichloromethane was subsequently washed with brine, dried over sodium carbonate and concentrated. The product, 5-(1H-benzoimidazol-2-yl)-2,4-dimethoxy-benzaldehyde (0.40 g, 47%), was obtain and used without further purification. 1H NMR (CDCl3) δ 10.32 (s, 1H), 10.27 (bs, 1H), 9.03 (s, 1H), 7.83 (d, J=9 Hz, 1H), 7.48–7.45 (m, 1H), 7.31–7.22 (m, 1H), 6.58 (s, 1H), 4.18 (s, 3H), 4.01 (s, 3H). MS m/z=282 (M+, 100%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](N)=[CH:4][C:3]=1[C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1.N([O-])=O.[Na+].[BrH:19]>O1CCOCC1.O.[Cu]Br>[Br:19][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:4]=1
Reactant: Br
Reactant: Nc1ccc(F)c(-c2cccnc2)c1
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Fc1ccc(Br)cc1-c1cccnc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
A warm solution of 4-fluoro-3-(pyridin-3-yl)phenylamine (3.64 g, 19.3 mmol) in 1,4-dioxane (10 mL) was treated with a solution of 48% aqueous hydrobromic acid (100 mL). The resulting suspension was cooled to 0° C. before being treated dropwise over 20 min with a solution of sodium nitrite (1.53 g, 22.2 mmol) in water (4 mL). After stirring at 0° C. for 2 h, a cooled (0° C.) solution of copper(I) bromide (8.31 g, 57.9 mmol) in 48% aqueous hydrobromic acid (30 ml) was added to the reaction which was stirred at 0° C. for 10 min then heated at 50° C. for 20 min. The reaction was cooled to ambient temperature, poured onto ice-cold conc. ammonia (500 mL) and the product was extracted into ethyl acetate (500 mL). The organics were washed with water (300 mL) and brine (300 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a dark oil. Purification by dry flash column chromatography on silica eluting with isohexane on a gradient of ethyl acetate (10%-30%) gave 3-(5-bromo-2-fluorophenyl)pyridine (3.1 g, 64%) as a white solid: δH (360 MHz, CDCl3) 7.09 (1H, dd, J 9 and 1), 7.37-7.40 (1H, m), 7.46-7.51 (1H, m), 7.56-7.59 (1H, m), 7.83-7.86 (1H, m), 8.63-8.65 (1H, m), 8.77-8.79 (1H, m).
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]([NH:18][C:19](=[O:27])[CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[S:17])=[CH:11][C:10]=2[F:28])[CH:5]=[CH:4][N:3]=1.CN1CC[O:33][CH2:32]C1.ClC(OC1C=CC=CC=1)=O.O.Cl.[O:48]=[C:49]1[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1>O1CCCC1.CN(C)C=O>[F:28][C:10]1[CH:11]=[C:12]([NH:15][C:16]([NH:18][C:19](=[O:27])[CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[S:17])[CH:13]=[CH:14][C:9]=1[O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:32]([N:52]2[CH2:53][CH2:54][C:49](=[O:48])[CH2:50][CH2:51]2)=[O:33])[CH:7]=1
Reactant: CN1CCOCC1
Reactant: O=C1CCNCC1
Reactant: Nc1cc(Oc2ccc(NC(=S)NC(=O)Cc3ccccc3)cc2F)ccn1
Agent: Cl
Agent: O=C(Cl)Oc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: O=C1CCN(C(=O)Nc2cc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)ccn2)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 63 %

Procedure:
2-Amino-4-{2-fluoro-4-[3-(2-phenylacetyl)thioureido]phenoxy}pyridine (100 mg) was dissolved in tetrahydrofuran (2.5 ml) under a nitrogen atmosphere, and then N-methylmorpholine (0.080 ml) and phenyl chloroformate (0.080 ml) were added dropwise thereto while cooling in an ice bath, followed by raising the temperature up to room temperature and stirring for 20 min. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then dissolved in N,N-dimethylformamide (2.5 ml), and then N-methylmorpholine (0.2 ml) and 4-oxopiperidine hydrochloride monohydrate (272 mg) were added thereto at room temperature, followed by stirring for 23 hrs. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (eluent; ethyl acetate). Fractions containing the target compound were concentrated under a reduced pressure to give a residue, which was dried in vacuum to provide the titled compound (83.1 mg, 63%) as white powder.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][NH:5][C@H:4]([C:7]2[NH:8][C:9]([C:12]3[CH:13]=[C:14]4[CH2:27][O:26][C:25]5[C:16]6=[C:17]([CH:22]=[C:23]([C:28]7[NH:32][C:31]([C@@H:33]8[CH2:37][C@H:36]([CH3:38])[CH2:35][NH:34]8)=[N:30][CH:29]=7)[CH:24]=5)[CH2:18][O:19][C:20]([CH:21]=3)=[C:15]46)=[CH:10][N:11]=2)[CH2:3]1.[CH3:39][O:40][C:41]([NH:43][C@@H:44]([CH:48]([CH3:50])[CH3:49])[C:45](O)=[O:46])=[O:42].[C:51]([O:55][C:56]([NH:58][C@H:59]([C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)[C:60]([OH:62])=O)=[O:57])([CH3:54])([CH3:53])[CH3:52].CCOC(C(C#N)=NOC(N1CCOCC1)=[N+](C)C)=O.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:39][O:40][C:41]([NH:43][C@@H:44]([CH:48]([CH3:50])[CH3:49])[C:45]([N:34]1[CH2:35][C@@H:36]([CH3:38])[CH2:37][C@H:33]1[C:31]1[NH:32][C:28]([C:23]2[CH:22]=[C:17]3[CH2:18][O:19][C:20]4[C:15]5=[C:14]([CH:13]=[C:12]([C:9]6[NH:8][C:7]([C@@H:4]7[CH2:3][C@H:2]([CH3:1])[CH2:6][N:5]7[C:60](=[O:62])[C@H:59]([NH:58][C:56]([O:55][C:51]([CH3:52])([CH3:53])[CH3:54])=[O:57])[C:63]7[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=7)=[N:11][CH:10]=6)[CH:21]=4)[CH2:27][O:26][C:25]([CH:24]=2)=[C:16]35)=[CH:29][N:30]=1)=[O:46])=[O:42]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccccc1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Reactant: C[C@@H]1CN[C@H](c2ncc(-c3cc4c5c(c3)OCc3cc(-c6cnc([C@@H]7C[C@H](C)CN7)[nH]6)cc(c3-5)OC4)[nH]2)C1
Agent: CCOC(=O)C(C#N)=NOC(N1CCOCC1)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N1C[C@@H](C)C[C@H]1c1ncc(-c2cc3c4c(c2)OCc2cc(-c5cnc([C@@H]6C[C@H](C)CN6C(=O)[C@H](NC(=O)OC(C)(C)C)c6ccccc6)[nH]5)cc(c2-4)OC3)[nH]1)C(C)C
Reaction time: 0.33 h

Procedure:
2,7-bis(2-((2S,4S)-4-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)-5,10-dihydrochromeno[5,4,3-cde]chromene was obtained as in Example OY. A mixture of (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (124 mg, 0.706 mmol), (R)-2-(tert-butoxycarbonylamino)-2-phenylacetic acid (177 mg, 0.706 mmol), COMU (665 mg, 1.55 mmol) in 3.7 mL DMF was allowed to preactivate for 20 minutes before it was added to 449 mg of the crude amine in 3.7 mL DMF with 0.74 mL DIPEA. Once starting material was consumed, by LCMS monitoring, the reaction mixture was neutralized with formic acid, diluted with methanol and purified by reverse phase HPLC three products, two homodimers and the heterodimer (S)-2-(methoxycarbonylamino)-1-((2S,4S)-2-(5-(7-(2-((2S,4S)-1-((R)-2-(t-butoxycarbonylamino)-2-phenylacetyl)-4-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)-5,10-dihydrochromeno[5,4,3-cde]chromen-2-yl)-1H-imidazol-2-yl)-4-methylpyrrolidin-1-yl)-3-methylbutan-1-one as the trifluoroacetate salts. The eluted fractions were concentrated under reduced pressure, basified with saturated sodium bicarbonate solution and extracted into dichloromethane. Concentration under reduced pressure gave product (86 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]([CH2:11][C@H:12]3[CH2:17][CH2:16][C@H:15]([CH3:18])[CH2:14][CH2:13]3)[CH:9]=[N:10][C:6]=2[CH:5]=[C:4]([Cl:19])[N:3]=1.P([O-])([O-])(O)=O.[Na+].[Na+].[Br:27]N1C(C)(C)C(=O)N(Br)C1=O>C1COCC1.CCOC(C)=O>[Br:27][C:9]1[N:8]([CH2:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([CH3:18])[CH2:14][CH2:13]2)[C:7]2[C:2]([Cl:1])=[N:3][C:4]([Cl:19])=[CH:5][C:6]=2[N:10]=1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: C[C@H]1CC[C@H](Cn2cnc3cc(Cl)nc(Cl)c32)CC1
Agent: O=P([O-])([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@H]1CC[C@H](Cn2c(Br)nc3cc(Cl)nc(Cl)c32)CC1
Temperature: 35 °C
Reaction time: 0.75 h

Procedure:
4,6-dichloro-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine (1 g, 3.35 mmol) was dissolved in THF (10 mL). Disodium hydrogen phosphate (1.43 g, 10.1 mmol) was added, and the reaction was warmed to 35° C. with stirring. 1,3-dibromo-5,5-dimethylhydantoin (1.15 g, 4.02 mmol) was added in 1 portion, and the reaction was continued with stirring at 35° C. After 45 minutes, the reaction was diluted with EtOAc (100 mL) and washed with aqueous NaHSO3 and brine. The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue on a silica gel column with 0 to 50% EtOAc/hexanes provided 2-bromo-4,6-dichloro-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:38])[C@H:10]([CH3:37])[CH2:11][C@H:12]([NH:26][C:27]([C:29]1[O:30][CH:31]=[C:32]([OH:36])[C:33](=[O:35])[CH:34]=1)=[O:28])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:39]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[CH2:1]([O:8][C:9](=[O:38])[C@H:10]([CH3:37])[CH2:11][C@H:12]([NH:26][C:27]([C:29]1[O:30][CH:31]=[C:32]([O:36][CH3:39])[C:33](=[O:35])[CH:34]=1)=[O:28])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cc(=O)c(O)co1)C(=O)OCc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1coc(C(=O)N[C@H](Cc2ccc(-c3ccccc3)cc2)C[C@@H](C)C(=O)OCc2ccccc2)cc1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Next, to a solution of (2R,4S)-5-biphenyl-4-yl-4-[(5-hydroxy-4-oxo-4H-pyran-2-carbonyl)-amino]-2-methyl-pentanoic acid benzyl ester (54 mg, 0.106 mmol) in DMF (1 mL) is added K2CO3 (29.2 mg, 0.211 mmol) and MeI (16.5 mg, 0.116 mmol), and the resulting mixture is stirred at room temperature overnight. Then ice/water is added and the mixture is extracted with EtOAc. The combined organic phases are washed with brine, dried over MgSO4, filtered and concentrated to give (2R,4S)-5-biphenyl-4-yl-4-[(5-methoxy-4-oxo-4H-pyran-2-carbonyl)-amino]-2-methyl-pentanoic acid benzyl ester which is used without further purification. HPLC Retention time 1.55 minutes (condition C): MS 526.3 (M+1).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:17])[O:12][CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:6][CH:5]=1)(=O)[CH3:2].[NH2:18][C:19]([NH2:21])=[S:20].II>C(O)(C)C.CCOC(C)=O>[NH2:21][C:19]1[S:20][CH:2]=[C:1]([C:4]2[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:17])[O:12][CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:6][CH:5]=2)[N:18]=1
Reactant: NC(N)=S
Reactant: CC(=O)c1ccc(NC(=O)OCC(C)C)cc1
Agent: II
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CC(C)COC(=O)Nc1ccc(-c2csc(N)n2)cc1
Yield: 51 %

Procedure:
To a solution of the product of the preceding section (a) (19 g, 80.75 mmol) in isopropanol (120 mL) was added thiourea (24.6 g, 323 mmol) and iodine (20.5 g, 161.5 mmol). The resulting mixture was heated at reflux for 7 h, then diluted with EtOAc, washed serially with H2O and saturated aqueous NaHCO3. The resulting solution was then treated with 4N aqueous HCl and Et2O and stirred vigorously. The precipitate was filtered and washed with Et2O. The collected solid was then treated with saturated aqueous NaHCO3 and extracted serially with EtOAc and CH2Cl2. The combined organic extracts were washed with H2O and brine, then dried (MgSO4) and concentrated under reduced pressure to yield 2-methylpropyl N-{4-(2-amino-4-thiazolyl)-phenyl}carbamate (12 g, 51% yield) as a pale yellow solid: 1H NMR (400 MHz, DMSO-d6) δ9.63 (s, 1H), 7.70 (d, 2H, J=8.9 Hz), 7.46 (d, 2H, J=8.7 Hz), 6.99 (s, 2H), 6.84 (s, 1H), 3.88 (d, 2H, J=6.9 Hz), 1.95 (m, 1H), 0.99 (d, 6H, J=6.9 Hz); MS (FAB) m/z 292 (MH)+. This product was used as such in the next reaction (section (c)).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:11])=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.Cl.[CH3:13][O:14][C:15]1[CH:28]=[CH:27][C:18]([C:19]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[O:20])=[CH:17][CH:16]=1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[CH3:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([C:19]([CH:21]2[CH2:26][CH2:25][N:24]([C:8]([C:5]3[CH:4]=[C:3]([CH3:11])[C:2]([Br:1])=[CH:7][N:6]=3)=[O:10])[CH2:23][CH2:22]2)=[O:20])=[CH:27][CH:28]=1
Reactant: COc1ccc(C(=O)C2CCNCC2)cc1
Reactant: Cc1cc(C(=O)O)ncc1Br
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(CC)CC
Product: COc1ccc(C(=O)C2CCN(C(=O)c3cc(C)c(Br)cn3)CC2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 89.8 %

Procedure:
To a mixture of 5-bromo-4-methylpyridine-2-carboxylic acid (0.400 g, 1.85 mmol, 1.0 eq) and 4-(4-methoxybenzoyl)piperidine hydrochloride (0.474 g, 1.85 mmol, 1.0 eq) was added dimethylformamide (10 mL) followed by triethylamine (0.64 mL, 4.36 mmol, 2.5 eq). HATU (0.774 g, 2.04 mmol, 1.1 eq) was added forming a yellow solution, which was stirred at room temperature for 1 day. The reaction was partitioned between EtOAc (120 mL) and water-NaHCO3 (1:1, 120 mL). The organics were further washed with brine (120 mL), water (120 mL) and brine (100 mL), dried (Na2SO4) and concentrated under reduced pressure. MPLC (0→10% MeOH—CH2Cl2) yielded the title compound (0.693 g, 89%) as a yellow oil; 1H nmr (CDCl3) δ 8.55 (1H, s, pyH-3 or H-6), 7.90 (2H, d, J 9.0 Hz, 2H of C6H4OMe), 7.48 (1H, s, pyH-3 or H-6), 6.91 (2H, d, J 9.0 Hz, 2H of C6H4OMe), 4.64 (1H, m, 1H of BzpipH-2, H-6), 4.01 (1H, m, 1H of BzpipH-2, H-6), 3.83 (3H, s, OCH3), 3.49 (1H, m, BzpipH-4), 3.23 (1H, m, 1H of BzpipH-2, H-6), 3.03 (1H, m, 1H of BzpipH-2, H-6), 2.39 (3H, s, pyCH3), 1.95 (1H, m, 1H of BzpipH-3, H-5), 1.86-1.75 (3H, s, 3H of BzpipH-3, H-5); m/z 417, 419 [M+H]+.