Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([N:14]2[CH2:18][CH2:17][C@@H:16]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH2:15]2)=[C:11]([F:13])[CH:12]=1)=[O:5])[CH3:2].C[CH2:28][O:29]C(C)=O>>[Si:20]([O:19][C@@H:16]1[CH2:17][CH2:18][N:14]([C:10]2[CH:9]=[CH:8][C:7]([N:6]3[CH2:2][C@H:1]([CH2:28][OH:29])[O:3][C:4]3=[O:5])=[CH:12][C:11]=2[F:13])[CH2:15]1)([C:23]([CH3:25])([CH3:24])[CH3:26])([CH3:22])[CH3:21]
Reactant: CCOC(=O)Nc1ccc(N2CC[C@@H](O[Si](C)(C)C(C)(C)C)C2)c(F)c1
Reactant: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CCN(c2ccc(N3C[C@H](CO)OC3=O)cc2F)C1

Procedure:
5-Ethoxycarbonylamino-2-((3R)-3-t-butyldimethylsilyloxy-1-pyrrolidinyl)fluorobenzene (29.4 g, 0.077 M) was treated in essentially the same way as the appropriate intermediate of Example 86, except that the product was isolated by extraction into EtOAc, and crude product purified by dry column chromatography on silica, eluting with a gradient from 0-20% MeOH in dichloromethane. Appropriate fractions were combined to give the desired product (29.6 g).
Reaction SMILES: Br[CH2:2][C@H:3]([CH3:10])[CH2:4][CH2:5][CH2:6][CH:7]([CH3:9])[CH3:8].C1(C)C=CC(S(O[CH2:21][CH2:22][C@@H:23]([CH3:30])[CH2:24][O:25][C:26]([CH3:29])([CH3:28])[CH3:27])(=O)=O)=CC=1>>[C:26]([O:25][CH2:24][C@H:23]([CH3:30])[CH2:22][CH2:21][CH2:2][C@H:3]([CH3:10])[CH2:4][CH2:5][CH2:6][CH:7]([CH3:9])[CH3:8])([CH3:27])([CH3:28])[CH3:29]
Reactant: Cc1ccc(S(=O)(=O)OCC[C@@H](C)COC(C)(C)C)cc1
Reactant: CC(C)CCC[C@@H](C)CBr
Product: CC(C)CCC[C@@H](C)CCC[C@@H](C)COC(C)(C)C

Procedure:
Reaction of the Grignard reagent, i.e., the magnesium salt of (R)-1-bromo-2,6-dimethylheptane with the (R)-(+ )-4-tert. butoxy-3-methyl-1-butanol p-toluenesulfonate was carried out using the procedure described in Example 12. The desired product (2R,6R)-(+)-1-tert. butoxy-2,6,10-trimethylundecane was obtained as a colorless oil, b.p. 90° C. (bath temperature) (0.1 mm Hg.).
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH2:7]Cl)=[CH:5][CH:6]=1.BrCC1CCCCO1.[O:17]=[C:18]1[C:26]2([C:30]3=[CH:31][C:32]4[O:36][CH2:35][O:34][C:33]=4[CH:37]=[C:29]3[O:28][CH2:27]2)[C:25]2[C:20](=[C:21]([C:38]#[N:39])[CH:22]=[CH:23][CH:24]=2)[NH:19]1.N1C2C(=CC=CC=2)C2(COC3C=C4C(=CC2=3)CCO4)C1=O>>[Cl:1][C:2]1[S:3][C:4]([CH2:7][N:19]2[C:20]3[C:25](=[CH:24][CH:23]=[CH:22][C:21]=3[C:38]#[N:39])[C:26]3([C:30]4=[CH:31][C:32]5[O:36][CH2:35][O:34][C:33]=5[CH:37]=[C:29]4[O:28][CH2:27]3)[C:18]2=[O:17])=[CH:5][CH:6]=1
Reactant: N#Cc1cccc2c1NC(=O)C21COc2cc3c(cc21)OCO3
Reactant: ClCc1ccc(Cl)s1
Agent: BrCC1CCCCO1
Agent: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Product: N#Cc1cccc2c1N(Cc1ccc(Cl)s1)C(=O)C21COc2cc3c(cc21)OCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 2-chloro-5-(chloromethyl)thiophene to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 2′-oxo-1,2′-dihydrospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indole]-7′-carbonitrile to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, 1′-[(5-chloro-2-thienyl)methyl]-2′-oxo-1′,2′-dihydrospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indole]-7′-carbonitrile was obtained (78%) as a colorless solid: mp 192-193° C. (diethyl ether); 1H NMR (300 MHz, DMSO-d6) δ 7.72 (dd, J=8.0, 1.1 Hz, 1H), 7.54 (dd, J=7.4, 1.1 Hz, 1H), 7.21 (dd, J=7.7, 7.7 Hz, 1H), 7.03 (s, 2H), 6.73 (s, 1H), 6.35 (s, 1H), 5.95 (dd, J=4.0, 0.7 Hz, 2H), 5.29 (d, J=1.5 Hz, 2H), 4.78 (dd, J=20.4, 9.6 Hz, 2H); 13C NMR (75 MHz, DMSO-d6) δ 177.0, 155.5, 148.7, 143.2, 141.8, 137.6, 133.6, 133.2, 128.8, 127.9, 126.6, 126.5, 123.7, 118.5, 116.9, 103.0, 101.5, 93.4, 92.6, 79.5, 56.4, 40.0; MS (ES+) m/z 437.3 (M+1), 439.3 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].C1C(=O)N([Br:18])C(=O)C1.OS(O)(=O)=O.O>ClCCl>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:18])=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)c1ccccc1N
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: O
Product: CC(=O)c1cc(Br)ccc1N
Temperature: 0 °C
Reaction time: 8 h
Yield: 58.1 %

Procedure:
To a mixture of 1-(2-aminophenyl)ethanone (5.0 g, 0.037 mol) in dichloromethane (60 mL) was added NBS (7.3 g, 0.04 mol). The resulting mixture was cooled to 0° C. followed by the addition of H2SO4 (0.05 mL). It was allowed to warm to room temperature and stirred overnight. To the reaction mixture was added water and extracted with dichloromethane, dried over MgSO4. The crude product was purified by column chromatography eluted with ethyl acetate/hexanes to afford the titled compound (4.6 g, 58%) as a yellow solid. m.p 87-89° C. 1H NMR (400 MHz, CDCl3): δ 2.56 (s, 3H), 6.31 (s, 2H), 7.56 (d, J=8.8 Hz, 1H), 7.33 (dd, J=2.4 Hz, 1H), 7.80 (d, J=2.4 Hz, 1H).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[OH:8].S=[C:10]1[CH2:14][S:13][C:12](=[O:15])[NH:11]1>C(O)C>[OH:8][C@@H:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C@H:2]1[NH:1][C:10]1[CH2:14][S:13][C:12](=[O:15])[N:11]=1
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: O=C1NC(=S)CS1
Solvent: CCO
Product: O=C1N=C(N[C@@H]2CCCC[C@H]2O)CS1
Temperature: 25 °C
Yield: 29.8 %

Procedure:
To a solution of trans-2-aminocyclohexanol (1.00 g) in ethanol (50 mL) was added 4-thioxo-1,3-thiazolidin-2-one (1.19 g), and the mixture was heated under reflux overnight. The reaction mixture was cooled to room temperature, the precipitate was removed, and the solvent of the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, tetrahydrofuran). The obtained powder was washed with ethyl acetate to give the title compound (554 mg).
Reaction SMILES: [ClH:1].C([N:9]1[CH2:14][CH2:13][O:12][CH:11]([CH2:15][N:16]([C:23]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:24])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10]1)C1C=CC=CC=1.[H][H]>O.C(O)C.[Pd]>[ClH:1].[O:25]([C:23]([N:16]([CH2:15][CH:11]1[O:12][CH2:13][CH2:14][NH:9][CH2:10]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:24])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=C(Oc1ccccc1)N(CC1CN(Cc2ccccc2)CCO1)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=C(Oc1ccccc1)N(CC1CNCCO1)c1ccccc1

Procedure:
A solution of 4-benzyl-2-(N-phenoxycarbonylanilino)methylmorpholine hydrochloride (9 g.) in water (75 ml.) and ethanol (200 ml.) is shaken in an atmosphere of hydrogen in the presence of palladium on charcoal catalyst (0.5 g.; 5%) until no further hydrogen is absorbed. The catalyst is removed by filtration and the filtrate is then evaporated to give a white residue which is recrystallised from methanol/ether to give 2-(N-phenoxycarbonylanilino)methylmorpholine hydrochloride, m.p. 179°-181°C.
Reaction SMILES: [NH2:1][C:2]1[C:13]([NH2:14])=[CH:12][C:5]([C:6]([NH:8][CH:9]2[CH2:11][CH2:10]2)=[O:7])=[C:4]([Cl:15])[CH:3]=1.[Cl:16][C:17]([Cl:23])([Cl:22])[C:18](=N)OC>C(O)(=O)C>[Cl:15][C:4]1[C:5]([C:6]([NH:8][CH:9]2[CH2:11][CH2:10]2)=[O:7])=[CH:12][C:13]2[N:14]=[C:18]([C:17]([Cl:23])([Cl:22])[Cl:16])[NH:1][C:2]=2[CH:3]=1
Reactant: Nc1cc(Cl)c(C(=O)NC2CC2)cc1N
Reactant: COC(=N)C(Cl)(Cl)Cl
Solvent: CC(=O)O
Product: O=C(NC1CC1)c1cc2nc(C(Cl)(Cl)Cl)[nH]c2cc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4,5-diamino-2-chloro-N-cyclopropylbenzamide (4.1 g, 18.2 mmol) in glacial acetic acid (50 ml) was added, at 0° C., methyl 2,2,2-trichloroacetimidate (2.21 ml, 18.2 mmol). The reaction mixture was stirred at room temperature for 16 h and then the solvent was removed under reduced pressure. The 6-chloro-N-cyclopropyl-2-(trichloromethyl)-1H-benzimidazole-5-carboxamide was used for Stage 4 directly without purification.
Reaction SMILES: [F:1][C:2]1([F:17])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-])=O)[CH2:4][CH2:3]1>CO.[Pd]>[F:17][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH2:14])[CH2:4][CH2:3]1
Reactant: O=[N+]([O-])c1ccccc1N1CCC(F)(F)CC1
Agent: [Pd]
Solvent: CO
Product: Nc1ccccc1N1CCC(F)(F)CC1
Yield: 69 %

Procedure:
Using a procedure similar to Example 3, step (c), 4,4-difluoro-1-(2-nitro-phenyl)-piperidine (128 mg, 0.520 mmol, as prepared in the previous step) was stirred with 80 mg 5% Pd—C in 4 mL of MeOH under H2 to afford 76 mg (69%) of the title compound as a dark oil, which was used immediately due to apparent instability. Mass spectrum (ESI, m/z): Calcd. for C11H14F2N2, 213.1 (M+H), found 213.1.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[CH2:20][CH2:19][CH2:18][C@H:17]([NH:21][CH3:22])[C:16]3=[O:23])[CH2:11][CH2:10]2)=[N:7][CH:8]=1)[CH3:2].[F:24][C:25]1[CH:30]=[C:29]([S:31]([CH3:34])(=[O:33])=[O:32])[C:28]([F:35])=[CH:27][C:26]=1F.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C>[F:24][C:25]1[CH:30]=[C:29]([S:31]([CH3:34])(=[O:33])=[O:32])[C:28]([F:35])=[CH:27][C:26]=1[N:21]([CH3:22])[C@H:17]1[CH2:18][CH2:19][CH2:20][N:15]([CH:12]2[CH2:11][CH2:10][N:9]([C:6]3[N:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][N:7]=3)[CH2:14][CH2:13]2)[C:16]1=[O:23]
Reactant: CCc1cnc(N2CCC(N3CCC[C@H](NC)C3=O)CC2)nc1
Reactant: CS(=O)(=O)c1cc(F)c(F)cc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1cnc(N2CCC(N3CCC[C@H](N(C)c4cc(F)c(S(C)(=O)=O)cc4F)C3=O)CC2)nc1
Temperature: 130 °C
Yield: 26.9 %

Procedure:
(S)-1′-(5-ethylpyrimidin-2-yl)-3-(methylamino)-1,4′-bipiperidin-2-one (0.040 g, 0.13 mmol), 1,2,4-trifluoro-5-(methylsulfonyl)benzene (Preparation C, 0.053 g, 0.25 mmol) and Na2CO3 (0.040 g, 0.38 mmol) were dissolved in DMF (1 mL) and heated at 130° C. overnight. The reaction was concentrated and the residue was purified using preparative TLC (100% EtOAc) to afford (S)-3-((2,5-difluoro-4-(methylsulfonyl)phenyl)(methyl)amino)-1′-(5-ethylpyrimidin-2-yl)-1,4′-bipiperidin-2-one (0.018 g, 0.035 mmol, 28% yield) as yellow solid. Mass spectrum (apci) m/z=508.3 (M+H).
Reaction SMILES: [C:1]([CH:3]1[CH:12]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[CH:5]([C:6]3[C:11]2=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:4]1)#[N:2].[CH2:19](N)[CH2:20][NH2:21].S.O>CCOCC>[NH:2]1[CH2:19][CH2:20][N:21]=[C:1]1[CH:3]1[CH:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[CH:5]([C:18]3[C:13]2=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:4]1
Reactant: NCCN
Reactant: N#CC1CC2c3ccccc3C1c1ccccc12
Agent: S
Solvent: CCOCC
Solvent: O
Product: c1ccc2c(c1)C1CC(C3=NCCN3)C2c2ccccc21
Temperature: 130 °C
Reaction time: 20 h
Yield: 91.6 %

Procedure:
A mixture of 11-cyano-9,10-dihydro-9,10-ethanoanthracene (4.6 g), ethylenediamine (1.5 g) and hydrogen sulfide (about 100 mg) is stirred at 130° C. for 20 hours. The reaction mixture is mixed with water and ether to be distributed in two layers. The ether layer is washed with water, dried, and evaporated to remove the ether. The residue is recrystallized from ether to give 11-(2-imidazolin-2-yl)-9,10-dihydro-9,10-ethanoanthracene (5.0 g) as crude crystals. IR (KBr), 1621 cm-1 (N--C=N).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.[NH2:17][CH2:18][C:19]1[CH:20]=[C:21]([NH:25][C:26](=[O:43])[C:27]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]3[O:40][CH:39]=[N:38][CH:37]=3)=[C:32]([O:41][CH3:42])[CH:31]=2)=[O:28])[CH:22]=[CH:23][CH:24]=1.C(N(CC)CC)C>CN(C)C=O.ClCCl>[C:1]([NH:17][CH2:18][C:19]1[CH:20]=[C:21]([NH:25][C:26](=[O:43])[C:27]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]3[O:40][CH:39]=[N:38][CH:37]=3)=[C:32]([O:41][CH3:42])[CH:31]=2)=[O:28])[CH:22]=[CH:23][CH:24]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(NC(=O)C(=O)Nc2cccc(CN)c2)ccc1-c1cnco1
Reactant: O=C(Cl)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc(NC(=O)C(=O)Nc2cccc(CNC(=O)c3ccccc3)c2)ccc1-c1cnco1
Temperature: 25 °C
Reaction time: 18 h
Yield: 45.5 %

Procedure:
29 mg (0.21 mmol) of benzoyl chloride were added to a solution of 100 mg (0.21 mmol) of N-[3-(aminomethyl)phenyl]-N′-[3-methoxy-4-(5-oxazolyl)phenyl]oxalamide trifluoroacetate, prepared as described in Example 3 above, and 46 mg (0.46 mmol) of triethylamine in a mixture of 2 ml of dimethylformamide and 5 ml of dichloromethane, and stirred at room temperature for 18 hours. The solution was washed with 2M hydrochloric acid and saturated sodium bicarbonate then dried over magnesium sulphate and evaporated to dryness. The residue was chromatographed on silica gel using ethyl acetate/petrol (2:1) for the elution. After trituration with diethyl ether there was obtained 45 mg of N-[3-(benzamidomethyl)phenyl]-N′-[3-methoxy-4-(5-oxazolyl)phenyl]oxalamide as a white solid. MS: m/e 471.0 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][N:10]([C:12](=[O:22])[CH2:13][CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11][C:4]=2[CH:3]=1.O.[NH2:24][NH2:25].C1C(O)=CC(C(O)=O)=C(O)C=1>O1CCOCC1>[NH:24]([C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][N:10]([C:12](=[O:22])[CH2:13][CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11][C:4]=2[CH:3]=1)[NH2:25]
Reactant: O=C(CCCc1ccccc1)N1CCc2nnc(Cl)cc2C1
Reactant: NN
Agent: O=C(O)c1cc(O)ccc1O
Solvent: C1COCCO1
Solvent: O
Product: NNc1cc2c(nn1)CCN(C(=O)CCCc1ccccc1)C2

Procedure:
11.8 g of 3-chloro-5,6,7,8-tetrahydro-6-(4-phenylbutyryl)pyrido[4,3-c]pyridazine and 60 cc of hydrazine hydrate are stirred at a bath temperature of 50° for 53 hours with the addition of 50 cc of dioxane. The mixture is worked up as described in Example 10. The gentisinate of the title compound has a M.P. of 203°-205° (decomp., from methanol/water 2:1).
Reaction SMILES: [C:1]1([C:7]2[N:11]([S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=3)(=[O:14])=[O:13])[CH:10]=[C:9]([CH2:22][N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:39][C:40]([NH:42][CH:43]1[CH2:45][CH2:44]1)=[O:41]>CN(C)C=O>[C:1]1([C:7]2[N:11]([S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:39][C:40]([NH:42][CH:43]4[CH2:45][CH2:44]4)=[O:41])[CH:16]=3)(=[O:13])=[O:14])[CH:10]=[C:9]([CH2:22][N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:28])[CH3:29])[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: CN(Cc1cc(C2=CCCCC2)n(S(=O)(=O)c2cccc(O)c2)c1)C(=O)OC(C)(C)C
Reactant: O=C(CBr)NC1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CN(Cc1cc(C2=CCCCC2)n(S(=O)(=O)c2cccc(OCC(=O)NC3CC3)c2)c1)C(=O)OC(C)(C)C
Reaction time: 16 h

Procedure:
tert-Butyl ((5-(cyclo ex-1-en-1-yl)-1-((3-hydroxyphenyl)sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate 7d (100 mg, 0.22 mmol) was dissolved in 20 mL of N,N-dimethylformamide, followed by addition of cesium carbonate (146 mg, 0.45 mmol) and 2-bromo-N-cyclopropyl-acetamide (79 mg, 0.45 mmol, prepared by a known method disclosed in “Journal of Medicinal Chemistry, 1987, 30(1), 20-24”), and then the reaction solution was stirred for 16 h. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography with elution system C to obtain the title product tert-butyl ((5-(cyclohex-1-en-1-yl)-1-((3-(2-(cyclopropylamino)-2-oxoethoxy)phenyl)sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate 7e (117 mg, a light yellow oily product) in 98% yield.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:7]=1[CH3:30])C.[NH2:32][NH2:33].O>C(O)C>[C:19]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:17][N:8]1[C:9]2[C:14](=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[C:6]([CH2:5][C:4]([NH:32][NH2:33])=[O:3])=[C:7]1[CH3:30]
Reactant: NN
Reactant: CCOC(=O)Cc1c(C)n(Cc2ccccc2-c2ccccc2)c2ccc(OC)cc12
Solvent: O
Solvent: CCO
Product: COc1ccc2c(c1)c(CC(=O)NN)c(C)n2Cc1ccccc1-c1ccccc1

Procedure:
A mixture of 1.18 g (2.86 mmol) of 1-([1,1-biphenyl]-2-ylmethyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid ethyl ester and 3 mL of hydrazine in 20 mL of ethanol was heated to maintain reflux for 16 hours. After cooling, water was added and the mixture was extracted with ethyl acetate. The ethyl acetate solution was washed with brine, dried (MgSO4), and concentrated to give 1.02 g of 1-([1,1′-biphenyl]-2-ylmethyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid hydrazide. A mixture of 576 mg (1.44 mmol) of this material and 300 mg of Raney Ni in 20 mL of ethanol was heated to maintain reflux for 3 hours. After cooling the solvent was decanted and the Raney Ni washed twice with methylene chloride. The combined organic solvents were concentrated at reduced pressure and the residue chromatographed on silica gel and eluted with ethyl acetate to give 369 mg (67% yield) of 1-([1,1′-biphenyl]-2-ylmethyl)-5-methoxy-2-methyl-1H-indole-3-acetamide.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].FC(F)(F)C([O-])=O.C[NH+]1CCCC(C([NH:24][C@H:25]([C:34]2[NH2+:35][C:36]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[CH:37][N:38]=2)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]C(=O)C)=O)C1.FC(F)(F)C([O-])=O.FC(F)(F)C([O-])=O.[NH3+][C@H](C1[NH2+]C(C2C=CC=CC=2)=CN=1)CCCCCC(=O)C.CCN(CC)CC.[CH3:87][O:88][C:89]1[CH:94]=[CH:93][C:92]([S:95](Cl)(=[O:97])=[O:96])=[CH:91][CH:90]=1>C(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].[CH3:87][O:88][C:89]1[CH:90]=[CH:91][C:92]([S:95]([NH:24][C@H:25]([C:34]2[NH2+:35][C:36]([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)=[CH:37][N:38]=2)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:3](=[O:5])[CH3:2])(=[O:97])=[O:96])=[CH:93][CH:94]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(=O)CCCCC[C@H](NC(=O)C1CCC[NH+](C)C1)C1=NC=C(c2ccccc2)[NH2+]1
Agent: CC(=O)CCCCC[C@H]([NH3+])C1=NC=C(c2ccccc2)[NH2+]1
Agent: O=C([O-])C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(S(=O)(=O)N[C@@H](CCCCCC(C)=O)C2=NC=C(c3ccccc3)[NH2+]2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of Example 1, A3 and Et3N (1.1 eq.) in DCM was added 4-methoxybenzene sulfonyl chloride (1.1 eq.). The reaction mixture was stirred at RT for 3 hr and the mixture was washed with sat. aq. NaHCO3. The organic phase was concentrated under reduced pressure and the crude residue was purified by preparative RP-HPLC, using H2O (0.1% TFA) and MeCN (+0.1% TFA) as eluents (column: C18). The desired fractions were lyophilized to afford the titled compound B1 as a colourless oil. 1H NMR (300 MHz, CD3CN) δ: 8.87 (1H, d, J=9.3 Hz), 7.60-7.52 (4H, m), 7.51-7.40 (3H, m), 7.31 (1H, s), 6.79-6.63 (2H, m), 4.78-4.65 (1H, m), 3.51 (3H, s), 2.37 (2H, t, J=7.3 Hz), 2.04 (3H, s), 1.89-1.78 (2H, m), 1.51-1.32 (3H, m), 1.31-1.14 (3H, m). MS (ES) C24H29N3O4S requires: 455, found: 456 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C@@H:18]([OH:21])[CH2:19][OH:20])=[CH:12][CH:11]=2)[C:5]([C:22]#[N:23])=[C:4]([S:24][CH2:25][C:26]2[N:27]=[C:28]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)[O:29][CH:30]=2)[N:3]=1.Cl.[CH3:39][NH:40][CH2:41][C:42]([O:44][CH3:45])=[O:43].C(N(CC)CC)C>CN(C=O)C>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([C:28]2[O:29][CH:30]=[C:26]([CH2:25][S:24][C:4]3[N:3]=[C:2]([N:40]([CH3:39])[CH2:41][C:42]([O:44][CH3:45])=[O:43])[C:7]([C:8]#[N:9])=[C:6]([C:10]4[CH:15]=[CH:14][C:13]([O:16][CH2:17][C@@H:18]([OH:21])[CH2:19][OH:20])=[CH:12][CH:11]=4)[C:5]=3[C:22]#[N:23])[N:27]=2)=[CH:32][CH:33]=1
Reactant: CNCC(=O)OC
Reactant: N#Cc1c(Cl)nc(SCc2coc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OC[C@@H](O)CO)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)CN(C)c1nc(SCc2coc(-c3ccc(Cl)cc3)n2)c(C#N)c(-c2ccc(OC[C@@H](O)CO)cc2)c1C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
108 mg (0.20 mmol) of the compound from Example 103A are dissolved in 3 ml of dry DMF, and 54 mg (0.39 mmol) of methyl N-methylglycinate hydrochloride and 59 mg (0.59 mmol) of triethylamine are added. The reaction mixture is stirred at RT for 8 h. The solvent is then removed on a rotary evaporator and the residue is purified directly by preparative HPLC (column: YMC GEL ODS-AQ S-5/15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5). After removal of the solvent on a rotary evaporator, the product is obtained as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[N:15]3[C:11](=[N:12][C:13]4[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=43)[S:10][CH:9]2[CH2:20][C:21]([OH:23])=[O:22])=[CH:4][CH:3]=1>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:15]3[C:11](=[N:12][C:13]4[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=43)[S:10][C:9]=2[CH2:20][C:21]([OH:23])=[O:22])=[CH:4][CH:3]=1
Reactant: O=C(O)CC1Sc2nc3ccccc3n2C1(O)c1ccc(Cl)cc1
Solvent: C1COCCO1
Product: O=C(O)Cc1sc2nc3ccccc3n2c1-c1ccc(Cl)cc1

Procedure:
3-(p-Chlorophenyl)-2,3-dihydro-3-hydroxy-thiazolo[3,2-a]-benzimidazole-2-acetic acid, (5.0 g.) is suspended in a solution of 100 ml. of a 6 N NCl and 200 ml. of dioxane. The mixture is heated at reflux for 18 hours. The solution is concentrated in vacuo to 50 ml. To the concentrate is added 200 ml. of water, and sufficient 4 N NaOH solution to dissolve all the solids. The alkaline solution is made acidic with acetic acid. The solid is collected, washed well with water and air-dried. The crude material is recrystallized from dimethoxyethane. The product (2.0 g.) melts at 242°-243° C.
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:14])[C@H:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[NH2:9])([CH3:5])([CH3:4])[CH3:3].C(N(CC)CC)C.Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>CN(C=O)C>[CH2:27]([O:26][C:24](=[O:25])[CH2:23][NH:9][C@@H:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[C:7]([O:6][C:2]([CH3:5])([CH3:4])[CH3:3])=[O:14])[CH3:28]
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)OC(=O)[C@@H](N)C(C)(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)CN[C@H](C(=O)OC(C)(C)C)C(C)(C)C
Reaction time: 1 h
Yield: 89.6 %

Procedure:
A solution of L-tert-leucine tert-butyl ester hydrochloride (5 g, 22.34 mmol) in DMF (25 mL) was treated with triethylamine (3.1 mL, 22.34 mmol) and the mixture was stirred for 1 hour. The reaction was filtered to remove solid salts, and the filtrate was treated with triethylamine (9.3 mL, 67.0 mmol) and ethyl bromoacetate (9.9 mL, 67.0 mmol), and the reaction was stirred for 3 hours at 25° C. The solvent was concentrated and the reaction was partitioned between dichloromethane and water. The organic phase was washed with brine and dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-20% ethyl acetate/hexane to give the title compound (5.47 g, 90% yield).
Reaction SMILES: [CH2:1]([N:8](C)[CH:9]1[CH2:15][N:14]([CH2:16][CH3:17])[CH2:13][CH2:12][N:11]2[C:18](=[O:27])[C:19]([OH:26])=[C:20]([C:22]([O:24][CH3:25])=[O:23])[N:21]=[C:10]12)C1C=CC=CC=1.Cl>CO.[Pd]>[CH2:16]([N:14]1[CH2:15][CH:9]([NH:8][CH3:1])[C:10]2=[N:21][C:20]([C:22]([O:24][CH3:25])=[O:23])=[C:19]([OH:26])[C:18](=[O:27])[N:11]2[CH2:12][CH2:13]1)[CH3:17]
Reactant: CCN1CCn2c(nc(C(=O)OC)c(O)c2=O)C(N(C)Cc2ccccc2)C1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCN1CCn2c(nc(C(=O)OC)c(O)c2=O)C(NC)C1

Procedure:
The compound of Step 1 was dissolved in MeOH and 6 N HCl (2.5 eq.) and stirred overnight under an H2 atmosphere in the presence of 10% Pd/C. The catalyst was then filtered off through celite, and the filtrate was concentrated under reduced pressure and triturated with diethyl ether to yield methyl 8-ethyl-3-hydroxy-10-(methylamino)-4-oxo-4,6,7,8,9,10-hexahydropyrimido[1,2-d][1,4]diazepine-2-carboxylate. MS (ES) C13H20N4O4 requires 296. Found: 297 (M+H+). The latter compound was taken in dichloromethane and treated with triethylamine (2.5 eq.) and methyl chloro(oxo)acetate (1.2 eq.). After stirring one hour at room temperature, solvent was removed under reduced pressure and residue was taken in methanol and treated with an excess of dimethyl amine (2 M solution in methanol) at room temperature overnight. Volatiles were evaporated under reduced pressure yielding title compound which was used without purification in the next step. MS (ES) C17H25N5O6 requires 395. Found: 396 (M+H+).