Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:25][CH2:26][CH2:27][CH2:28][N:29]4[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]4)=[C:21](F)[CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CS(C)=O.[O:40]([CH3:42])[K].CO>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:25][CH2:26][CH2:27][CH2:28][N:29]4[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]4)=[C:21]([O:40][CH3:42])[CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CO[K]
Reactant: CN1CCN(CCCOc2cc3ncnc(C4CCN(C(=O)OC(C)(C)C)CC4)c3cc2F)CC1
Solvent: CO
Solvent: ClCCl
Solvent: CS(C)=O
Product: COc1cc2c(C3CCN(C(=O)OC(C)(C)C)CC3)ncnc2cc1OCCCN1CCN(C)CC1
Temperature: 100 °C
Reaction time: 9 h
Yield: 55 %

Procedure:
A mixture of 4-{6-Fluoro-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinazolin-4-yl}-piperidine-1-carboxylic acid tert-butyl ester (32.6 mg, 66.9 μmol), as prepared in Example 90d, DMSO (50 μL), and 0.31M KOMe/MeOH (270 μL, 83.9 μmol KOMe in 6.4 mmol MeOH) was stirred at 100° C. for 9 hr, and then 110° C. for 2 hr. The resulting pale yellow homogeneous solution was allowed to cool to rt, diluted with DCM (2 mL), and washed with 4M NaCl (1×2 mL). The aq layer was back-extracted with DCM (1×2 mL), and the combined organic layers were dried (Na2SO4) and concentrated. Purification of the residue by silica flash chromatography (1:2 hex/EtOAc→1:2 hex/EtOAc/3% DMEA→9:1 EtOAc/acetone/3% DMEA eluent) afforded the title compound (18.4 mg, 55%). NOe experiments support the assigned regioisomer. Select 1H-NMR resonances and nOes (300 MHz, CDCl3) δ 7.34 (s, 1H), 7.24 (s, 1H), 4.04 (s, 3H), 3.51 (m, 1H). Irradiation of the diagnostic methine proton at δ 3.51 generates an nOe to the quinazoline C5 proton at δ 7.24, but not to the quinazoline C8 proton at δ 7.34. Irradiation of the methoxy protons at δ 4.04 generates an nOe to the C5 proton at δ 7.24, but not to the C8 proton at δ 7.34. This indicates methoxy substitution at C6 of the quinazoline. LC/MS (ESI): calcd mass 499.3, found 500.4 (MH)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[C:12]([O:17][CH2:18][CH2:19][CH2:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)[CH:5]=[CH:4][N:3]=1.Cl.[CH2:26]([O:28][C:29]([CH:31]1[CH2:36][CH2:35][CH:34]([NH2:37])[CH2:33][CH2:32]1)=[O:30])C.C([O-])([O-])=O.[K+].[K+].O>CN1C(=O)CCC1>[CH3:26][O:28][C:29]([CH:31]1[CH2:36][CH2:35][CH:34]([NH:37][C:2]2[N:7]=[C:6]([N:8]3[C:16]4[C:11](=[C:12]([O:17][CH2:18][CH2:19][CH2:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH:13]=[CH:14][CH:15]=4)[CH:10]=[CH:9]3)[CH:5]=[CH:4][N:3]=2)[CH2:33][CH2:32]1)=[O:30]
Reactant: CCOC(=O)C1CCC(N)CC1
Reactant: CS(=O)(=O)CCCOc1cccc2c1ccn2-c1ccnc(Cl)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: COC(=O)C1CCC(Nc2nccc(-n3ccc4c(OCCCS(C)(=O)=O)cccc43)n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
1-(2-Chloro-pyrimidin-4-yl)-4-(3-methanesulfonyl-propoxy)-1H-indole (300 g), 4-amino-cyclohexanecarboxylic acid ethyl ester HCl salt (155 g), and K2CO3(170 g) in NMP (2.35 L) were stirred at 80° C. for 5 h and then stirred overnight at room temperature. The reaction mixture was then stirred on an ice bath, and 2.5 L water was slowly added while stirring, and cooling continued until completion of the exothermic reaction. Upon cooling, the mixture was filtered, and resulting solid was rinsed with H2O and dried in vacuo overnight to yield 4-{4-[4-(3-methanesulfonyl-propoxy)-indol-1-yl]-pyrimidin-2-ylamino}-cyclohexanecarboxylic acid methyl ester (97%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]([CH:12]2[CH2:14][CH2:13]2)([CH3:11])[CH:9]=O)=[CH:4][CH:3]=1.[NH2:15][OH:16].[Cl-].[Na+].C(OC(C)C)(=O)C>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]([CH:12]2[CH2:14][CH2:13]2)([CH3:11])[CH:9]=[N:15][OH:16])=[CH:4][CH:3]=1
Reactant: NO
Reactant: C[C@](C=O)(c1ccc(Br)cc1)C1CC1
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)OC(C)C
Solvent: O
Product: C[C@](C=NO)(c1ccc(Br)cc1)C1CC1
Temperature: 20 °C
Reaction time: 2 h
Yield: 99.7 %

Procedure:
To a 500 mL reactor is charged the crude solution of (R)-2-(4-bromophenyl)-2-cyclopropylpropanal (7, 230 g, 11.9 wt %, 108.1 mmol, 1.00 equiv). The batch is reduced to 75 mL (3 vols) via vacuum distillation (external temperature NMT 55° C.). To the batch is charged ethanol (denatured, 78.9 g, 100 mL, 4 vols). The batch is reduced to 75 mL (3 vols) via vacuum distillation (external temperature NMT 55° C.). To the batch is charged ethanol (denatured, 39.5 g, 50 mL, 2 vols). The batch temperature is adjusted to an internal temperature of 10±5° C. To the batch is charged 50 wt % Hydroxylamine (10.7 g, 162.2 mmol, 1.50 equiv) at a rate to maintain the internal temperature of the batch <30° C. The batch is then agitated at an internal temperature of 20±5° C. for 2 h. An HPLC sample is removed to determine conversion (target >97 A % conversion 220 nm, for this batch: >99.5 A % conversion). To a separate vessel (vessel 2) is prepared the 5 wt % aqueous sodium chloride solution by dissolving sodium chloride (7.5 g) in water (142.5 g). To the batch is charged isopropyl acetate (157 g, 180 mL, 7 vols) and 5 wt % aqueous sodium chloride (75 g, ˜3 vols, vessel 2). The batch is agitated for 20 min and then the layers are allowed to settle. The aqueous layer is cut. To the batch is charged 5 wt % aqueous sodium chloride (75 g, ˜3 vols, vessel 2). The batch is agitated for 20 min and then the layers are allowed to settle. The aqueous layer is cut. The batch volume is adjusted to 2-3 vols (50-75 mL) via vacuum distillation (external temperature NMT 55° C.). To the batch is charged acetonitrile (39.3 g, 50 mL, ˜2 vols). The batch volume is adjusted to 2 vols (50-75 mL) via vacuum distillation (external temperature NMT 55° C.). The batch was drained and the reactor rinsed with acetonitrile (3.9 g, 5 mL). The rinse is combined with the original batch and the resulting solution reduced to ˜50 mL via vacuum distillation. The mass of the resulting solution: 44.4 g and the Proton NMR wt % assay (with dimethyl fumarate as an internal standard) is 65 wt % (28.9 g, 99.5% yield) of (R)-2-(4-bromophenyl)-2-cyclopropylpropanal oxime (8). The solution is used as is for the following step.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: Nc1ccccc1
Solvent: CCO
Product: Clc1nc(Nc2ccccc2)c2[nH]cnc2n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 98.1 %

Procedure:
To a solution of 2,6-dichloropurine (20 g, 106 mmol) in 400 ml of ethanol are added 36.5 ml of aniline (400 mmol) and the resulting solution is kept at 50° C. under magnetic stirring for 12 h. After cooling to RT, the mixture is filtered, washed with 2×50 ml of ethanol and dried at 50° C. under HV to give 2-chloro-6-(phenyl-amino)-purine as a yellow powder (25.5 g, 104 mmoles) in 98% yield. Rf=0.57 (CH2Cl2/MeOH (95/5); m.p. decomp. >290° C.; ESI-MS: 246 (M+H)+; 1H—NMR (d6-DMSO, 200 MHz, TMS): 7.1 ppm (t, 1H, J=8 Hz, H6), 7.35 ppm (t, 2H, J=8 Hz, H5), 7.8 ppm (d, 2H, J=8 Hz, H4), 8.3 ppm (s, 1H, H2), 10.1 ppm (s, 1H, H3),
Reaction SMILES: [CH3:1][O:2][C@H:3]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C:5](=[CH:6][C:7](=[O:23])[C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C:12]2=[O:22])[CH2:4]1.[BH4-].[Na+]>C(Cl)Cl.CO>[CH3:1][O:2][C@H:3]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C:5](=[CH:6][C@H:7]([OH:23])[C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[OH:22])[CH2:4]1
Reactant: CO[C@H]1CC[C@@]2(C)C(=CC(=O)[C@@H]3[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]32)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CO[C@H]1CC[C@@]2(C)C(=C[C@H](O)[C@H]3[C@@H]4CC[C@H](O)[C@@]4(C)CC[C@@H]32)C1

Procedure:
24 was prepared by reduction of 3β-methoxyandrost-5-ene-7,17-dione 20, with sodium borohydride in a mixture of methylene dichloride-methanol at room temperature. The product was purified by column chromatography.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:21][N:5]2[C:6](=[O:20])[N:7]([C:9]3[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=3)[CH2:8][C@@H:4]2[CH2:3]1.[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[S:29](Cl)(=[O:31])=[O:30]>>[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[S:29]([NH:1][C@H:2]1[CH2:21][N:5]2[C:6](=[O:20])[N:7]([C:9]3[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:17])[F:18])=[CH:11][CH:10]=3)[CH2:8][C@@H:4]2[CH2:3]1)(=[O:31])=[O:30]
Reactant: N[C@@H]1C[C@H]2CN(c3ccc(OC(F)(F)F)cc3)C(=O)N2C1
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Product: O=C1N(c2ccc(OC(F)(F)F)cc2)C[C@@H]2C[C@@H](NS(=O)(=O)c3ccccc3Cl)CN12
Yield: 27 %

Procedure:
In analogy to the procedure described for the synthesis of 2-Chloro-N-[(6R,7aS)-3-oxo-2-(4-trifluoromethoxy-phenyl)-hexahydro-pyrrolo[1,2-c]imidazol-6-yl]-benzamide (example 1, step i) the title compound was prepared from (6R,7aS)-6-Amino-2-(4-trifluoromethoxy-phenyl)-hexahydro-pyrrolo[1,2-c]imidazol-3-one (example 1, step h) and 2-chlorobenzene-1-sulfonyl chloride to yield 27% the title compound. 1H NMR (300 MHz, CDCl3): δ 8.13 (d, 1H, J=7.2 Hz), 7.58-7.45 (m, 6H), 7.19 (d, 2H, J=9.0 Hz), 5.33 (d, 1H, J=6.3 Hz), 4.06-3.98 (m, 3H), 3.94-3.85 (m, 1H), 3.66 (d, 1H, J=6.9 Hz), 2.94 (dd, 1H, J1=12.9 Hz, J2=3.6 Hz), 2.19-2.12 (m, 1H), 1.74-1.64 (m, 1H); LC-MS: 476.0 [M+1]+.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:9][C@H:8]([N:10]2[CH:18]=[N:17][C:16]3[C:11]2=[N:12][CH:13]=[N:14][C:15]=3[NH:19][C@@H:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22][CH2:21]2)[O:7][C@@H:6]1[CH2:29][OH:30])(=[O:3])[CH3:2].Cl[S:32]([NH2:35])(=[O:34])=[O:33]>>[C:1]([O:4][C@H:5]1[CH2:9][C@H:8]([N:10]2[CH:18]=[N:17][C:16]3[C:11]2=[N:12][CH:13]=[N:14][C:15]=3[NH:19][C@@H:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22][CH2:21]2)[O:7][C@@H:6]1[CH2:29][O:30][S:32]([NH2:35])(=[O:34])=[O:33])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1C[C@H](n2cnc3c(N[C@H]4CCc5ccccc54)ncnc32)O[C@@H]1CO
Reactant: NS(=O)(=O)Cl
Product: CC(=O)O[C@H]1C[C@H](n2cnc3c(N[C@H]4CCc5ccccc54)ncnc32)O[C@@H]1COS(N)(=O)=O
Yield: 74 %

Procedure:
(2R,3S,5R)-5-{6-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-9H-purin-9-yl}-2-(hydroxymethyl)tetrahydrofuran-3-yl acetate (199 mg, 0.29 mmol) was treated with chlorosulfonamide as described in Example 39, step c. The product was purified by flash chromatography (0 to 5% MeOH/CH2Cl2) to afford 105 mg (74%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]2[C:13](F)([F:15])[C:12](=[O:17])[CH:11]=[CH:10][C:9]=2[N:8]=[CH:7][C:6]=1[O:18][C:19](=[O:21])[CH3:20])=[O:4]>[Pd].CO>[CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:17])[C:13]=2[F:15])[N:8]=[CH:7][C:6]=1[O:18][C:19](=[O:21])[CH3:20])=[O:4]
Reactant: COC(=O)c1c(OC(C)=O)cnc2c1C(F)(F)C(=O)C=C2
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1c(OC(C)=O)cnc2ccc(O)c(F)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.2 %

Procedure:
10% Palladium on activated carbon (178 mg, 0.17 mmol, 0.015 eq) is added at room temperature to a stirred solution of 3-acetoxy-5,5-difluoro-6-oxo-5,6-dihydro-quinoline-4-carboxylic acid methyl ester (2.27 g, 11.32 mmol, 1.0 eq) in methanol (50 mL). The resulting mixture is stirred under hydrogen flow (1 bar) at room temperature for 2 hours. The catalyst is then removed by filtration and the solution is concentrated to afford 3-acetoxy-5-fluoro-6-hydroxy-quinoline-4-carboxylic acid methyl ester as a light yellow semisolid (2.03 g, 95% yield) which is directly engaged in the next step.
Reaction SMILES: C[O:2][C:3](=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]=1[CH3:14].CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.Br[CH2:35][C:36]1[CH:41]=[CH:40][C:39]([S:42]([CH3:45])(=[O:44])=[O:43])=[C:38]([C:46]([F:49])([F:48])[F:47])[CH:37]=1>CN(C=O)C>[CH3:45][S:42]([C:39]1[CH:40]=[CH:41][C:36]([CH2:35][N:7]2[C:8]3=[N:9][CH:10]=[CH:11][CH:12]=[C:13]3[C:5]([CH2:4][C:3]([OH:2])=[O:15])=[C:6]2[CH3:14])=[CH:37][C:38]=1[C:46]([F:47])([F:49])[F:48])(=[O:44])=[O:43]
Reactant: CS(=O)(=O)c1ccc(CBr)cc1C(F)(F)F
Reactant: COC(=O)Cc1c(C)[nH]c2ncccc12
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: CN(C)C=O
Product: Cc1c(CC(=O)O)c2cccnc2n1Cc1ccc(S(C)(=O)=O)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of (2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid methyl ester ((12.8 g, 62.8 mmol) in dry DMF (200 ml) under an inert atmosphere of Argon is added dropwise, BEMP (19.9 ml, 69.1 mmol) over five minutes. After stirring at room temperature for 1 hour, the resulting solution is added dropwise to a stirred solution of 1-bromomethyl-4-methanesulfonyl-3-trifluoromethyl-benzene (23.9 g, 75.4 mmol) and stirred for 18 hours. The reaction is concentrated in vacuo with toluene and the resulting oil is purified by chromatography on silica eluting with iso-hexane/acetone (15:1). The crude is further purified by dissolving in hot ethyl acetate and refluxing in the presence of charcoal for 5 minutes. The solution is filtered and the solvent is removed in vacuo. The resulting solid is re-crystallized from ethyl acetate/iso-hexane to yield the titled product as a white solid. (MH+ 441)
Reaction SMILES: [CH2:1]([C:8]1[CH:17]=[C:16]2[C:11]([C:12]([OH:31])=[C:13]([C:26]([O:28]CC)=O)[C:14](=[O:25])[N:15]2[CH2:18][C:19]2[N:20]([CH3:24])[CH:21]=[CH:22][N:23]=2)=[N:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:32]1([NH2:35])[CH2:34][CH2:33]1>>[CH2:1]([C:8]1[CH:17]=[C:16]2[C:11]([C:12]([OH:31])=[C:13]([C:26]([NH:35][CH:32]3[CH2:34][CH2:33]3)=[O:28])[C:14](=[O:25])[N:15]2[CH2:18][C:19]2[N:20]([CH3:24])[CH:21]=[CH:22][N:23]=2)=[N:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccccc3)cc2n(Cc2nccn2C)c1=O
Reactant: NC1CC1
Product: Cn1ccnc1Cn1c(=O)c(C(=O)NC2CC2)c(O)c2ncc(Cc3ccccc3)cc21

Procedure:
This compound was prepared from ethyl 7-benzyl-4-hydroxy-1-[(1-methyl-1H-imidazol-2-yl)methyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and cyclopropylamine using methods similar to those described in Example 11. The product was obtained as a white solid: 1H NMR (CDCl3) δ 10.02 (1H, br), 8.57 (1H, s), 8.45 (1H, br s), 7.30-7.21 (5H, m), 7.01 (1H, br s), 6.83 (1H, s), 5.69 (2H, br), 4.17 (2H, s), 3.67 (3H, s), 2.95 (1H, m), 0.91 (2H, m), 0.71 (2H, m); HRMS calcd for C24H23N5O3+H+: 430.1879. Found: 430.1877.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]3[N:21]([CH2:22][CH2:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:20](=[O:31])[C@H:19]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[CH2:18]3)=[C:11]([N+:37]([O-])=O)[CH:10]=2)=[CH:5][CH:4]=1)#[N:2].CN(C)C=O>C(O)C.[Pd]>[NH2:37][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH:14]=[CH:13][C:12]=1[O:15][CH2:16][C@H:17]1[N:21]([CH2:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:20](=[O:31])[C@H:19]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[CH2:18]1
Reactant: COC(=O)C[C@@H]1C[C@@H](COc2ccc(-c3ccc(C#N)cc3)cc2[N+](=O)[O-])N(CCCc2ccccc2)C1=O
Agent: [Pd]
Solvent: CCO
Solvent: CN(C)C=O
Product: COC(=O)C[C@@H]1C[C@@H](COc2ccc(-c3ccc(C#N)cc3)cc2N)N(CCCc2ccccc2)C1=O

Procedure:
4 g of (3S,5S)-5-[(4'-cyano-3-nitro-4-biphenylyl)oxymethyl]-3-[(methoxycarbonyl)methyl]-1-(3-phenylpropyl)-2-pyrrolidinone are hydrogenated in 40 ml of ethanol and 10 ml of dimethylformamide with 1.5 g of palladium (10% on activated charcoal) under a hydrogen pressure of 3 bar at ambient temperature. After 40 minutes the catalyst is removed by suction filtering and the filtrate is evaporated down. The residue is divided between water and methylene chloride, the organic phase is separated off, dried with magnesium sulphate and evaporated down. Column chromatography on silica gel with methylene chloride/ethyl acetate (4:1) yields 2.9 g (77% of theory) of the desired compound. Melting point: 111°-112° C. Rf value: 0.37 (silica gel; 1,2-dichloroethane/ethyl acetate=3:1) Calculated: C 72.41 H 6.28 N 8.45 Found: 72.31 6.54 8.27
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9](=[O:38])[NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][N:19]2[CH2:23][C:22](=[O:24])[N:21](CC3C=CC(OC)=CC=3OC)[S:20]2(=[O:37])=[O:36])=[CH:14][CH:13]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH2:8][C:9]([NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][N:19]2[CH2:23][C:22](=[O:24])[NH:21][S:20]2(=[O:36])=[O:37])=[CH:14][CH:13]=1)=[O:38]
Reactant: COc1ccc(CN2C(=O)CN(Cc3ccc(CNC(=O)CNC(=O)OC(C)(C)C)cc3)S2(=O)=O)c(OC)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCC(=O)NCc1ccc(CN2CC(=O)NS2(=O)=O)cc1
Reaction time: 0.5 h

Procedure:
The title C compound, ({4-[5-(2,4-dimethoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]-benzylcarbamoyl}-methyl)-carbamic acid t-butyl ester (80 mg, 0.14 mmol) is stirred in equal volumes of CH2Cl2 and TFA (4 mL) for 16 h. The volatiles are evaporated and the residue is stirred in equal volumes of MeCN/water (5 mL) for 30 min. The mixture is filtered through a 0.2μ Acrodisc and the solvents are evaporated. The solid is washed with Et2O and dried to afford 2-amino-N-[4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzyl]-acetamide as a white solid: [M−1]−=311.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[N:11][N:12]3[CH:17]=[CH:16][N:15]=[CH:14][C:13]=23)O1.[Cl:19][C:20]1[N:25]=[C:24](C2C=NN3C=CC=CC=23)[CH:23]=[N:22][CH:21]=1>>[Cl:19][C:20]1[N:25]=[C:24]([C:9]2[CH:10]=[N:11][N:12]3[CH:17]=[CH:16][N:15]=[CH:14][C:13]=23)[CH:23]=[N:22][CH:21]=1
Reactant: Clc1cncc(-c2cnn3ccccc23)n1
Reactant: CC1(C)OB(c2cnn3ccncc23)OC1(C)C
Product: Clc1cncc(-c2cnn3ccncc23)n1
Yield: 28 %

Procedure:
Obtained as a yellow solid (28% yield, two steps) from 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyrazine (Preparation 29a) according to the experimental procedure as described in Preparation 27b followed by purification by flash chromatography (2:8 ethyl acetate/hexane).
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[N:6][CH:5]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[Cl:21])[C:4]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23].[NH:27]1[CH2:32][CH2:31][O:30][C@H:29]([CH2:33][OH:34])[CH2:28]1>>[Cl:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[CH:5]1[C:4]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:3]([CH2:2][N:27]2[CH2:32][CH2:31][O:30][C@H:29]([CH2:33][OH:34])[CH2:28]2)[NH:8][C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[N:6]1
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Cl
Reactant: OC[C@@H]1CNCCO1
Product: CCOC(=O)C1=C(CN2CCO[C@H](CO)C2)NC(c2nccs2)=NC1c1ccc(F)cc1Cl
Yield: 30.3 %

Procedure:
Ethyl 6-(bromomethyl)-4-(2-chloro-4-fluorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.92 g, 2 mmol) was reacted with (S)-morpholin-2-ylmethanol (0.34 g, 2.2 mmol) according to the procedure as described in Example 25, Step B to give the title compound as a yellow solid (0.30 g, 30%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: O.[NH:2]1[CH2:8][C:6](=[O:7])[NH:5][C:3]1=[O:4].[CH:9]1([CH:15]=O)[CH2:14][CH2:13][CH:12]=[CH:11][CH2:10]1.C(CN)O>C(O)(C)C>[CH:9]1([CH:15]=[C:8]2[NH:2][C:3](=[O:4])[NH:5][C:6]2=[O:7])[CH2:14][CH2:13][CH:12]=[CH:11][CH2:10]1
Reactant: O=C1CNC(=O)N1
Reactant: O=CC1CC=CCC1
Solvent: CC(C)O
Solvent: O
Solvent: NCCO
Product: O=C1NC(=O)C(=CC2CC=CCC2)N1
Temperature: 120 °C
Yield: 87.1 %

Procedure:
Fifty milliliters of water, 20 ml of isopropyl alcohol, 20.00 g of hydantoin, 24.22 g of 3-cyclohexene-1-carbaldehyde and 6.10 g of monoethanolamine were placed in a reactor equipped with a mechanical stirrer and a reflux condenser, the mixture was stirred in an oil bath at 120° C. while refluxing. After 3 hours of continued heating and stirring, the solution was cooled to 10° C., and the precipitated crystals were collected by filtration. These were suspended in 100 ml of a mixed solution of water and isopropyl alcohol (volumetric ratio=2:5), after which the crystals were again collected by filtration and dried under reduced pressure at 40° C. overnight, to obtain 33.45 g of 5-(3-cyclohexene-1-yl)methylenehydantoin. The yield was 87.0%. The crude crystals were recrystallized from ethanol to obtain a pure product.
Reaction SMILES: [CH:1]1([C@@H:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:24]=4[F:31])=[C:19]([C@H:32](F)[C:33]([CH3:36])([CH3:35])[CH3:34])[CH:18]=3)[C:10]=2[F:38])[CH2:5][C:6]([OH:8])=[O:7])[CH2:3][CH2:2]1.C1([C@@H](C2C=CC=C(OCC3C=CC(C4C=C(OC)C=CC=4F)=C([C@@H](F)C(C)(C)C)C=3)C=2F)C[C:44](O)=[O:45])CC1.C1([C@H](C2C=CC=C(OCC3C=CC(C4C=C(OC)C=CC=4F)=C([C@H](F)C(C)(C)C)C=3)C=2F)CC(O)=O)CC1.C1([C@H](C2C=CC=C(OCC3C=CC(C4C=C(OC)C=CC=4F)=C([C@@H](F)C(C)(C)C)C=3)C=2F)CC(O)=O)CC1>>[CH:1]1([C@H:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:24]=4[F:31])=[C:19]([C@@H:32]([O:45][CH3:44])[C:33]([CH3:34])([CH3:35])[CH3:36])[CH:18]=3)[C:10]=2[F:38])[CH2:5][C:6]([OH:8])=[O:7])[CH2:2][CH2:3]1
Reactant: COc1ccc(F)c(-c2ccc(COc3cccc([C@@H](CC(=O)O)C4CC4)c3F)cc2[C@@H](F)C(C)(C)C)c1
Reactant: COc1ccc(F)c(-c2ccc(COc3cccc([C@@H](CC(=O)O)C4CC4)c3F)cc2[C@H](F)C(C)(C)C)c1
Agent: COc1ccc(F)c(-c2ccc(COc3cccc([C@H](CC(=O)O)C4CC4)c3F)cc2[C@@H](F)C(C)(C)C)c1
Agent: COc1ccc(F)c(-c2ccc(COc3cccc([C@H](CC(=O)O)C4CC4)c3F)cc2[C@H](F)C(C)(C)C)c1
Product: COc1ccc(F)c(-c2ccc(COc3cccc([C@H](CC(=O)O)C4CC4)c3F)cc2[C@@H](OC)C(C)(C)C)c1
Yield: 88 %

Procedure:
(3S)-3-Cyclopropyl-3-(2-fluoro-3-(((2′-fluoro-2-((1R)-1-fluoro-2,2-dimethylpropyl)-5′-(methyloxy)-1,1′-biphenyl-4-yl)methyl)oxy)phenyl)propanoic acid or (3S)-3-cyclopropyl-3-(2-fluoro-3-(((2′-fluoro-2-((1S)-1-fluoro-2,2-dimethylpropyl)-5′-(methyloxy)-1,1′-biphenyl-4-yl)methyl)oxy)phenyl)propanoic acid or (3R)-3-cyclopropyl-3-(2-fluoro-3-(((2′-fluoro-2-((1R)-1-fluoro-2,2-dimethylpropyl)-5′-(methyloxy)-1,1′-biphenyl-4-yl)methyl)oxy)phenyl)propanoic acid or (3R)-3-cyclopropyl-3-(2-fluoro-3-(((2′-fluoro-2-((1S)-1-fluoro-2,2-dimethylpropyl)-5′-(methyloxy)-1,1′-biphenyl-4-yl)methyl)oxy)phenyl)propanoic acid (83.9). The alkylation and hydrolysis were conducted in an analogous manner to Example 66.6 (using 83.B and 66.30G or 66.30H derived from peak two from the chiral separation of 66.30D from the OD-column, described herein) to yield 83.8 (0.0256 g, 88% yield). MS ESI (neg.) m/e: 525.3 (M−H)+.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([O:9][CH3:10])[C:5]([NH2:8])=[N:6][CH:7]=1.[Cl:11][C:12]1[CH:13]=[C:14]([S:19](Cl)(=[O:21])=[O:20])[CH:15]=[CH:16][C:17]=1[Cl:18]>>[Br:1][C:2]1[N:3]=[C:4]([O:9][CH3:10])[C:5]([NH:8][S:19]([C:14]2[CH:15]=[CH:16][C:17]([Cl:18])=[C:12]([Cl:11])[CH:13]=2)(=[O:21])=[O:20])=[N:6][CH:7]=1
Reactant: COc1nc(Br)cnc1N
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Product: COc1nc(Br)cnc1NS(=O)(=O)c1ccc(Cl)c(Cl)c1

Procedure:
Prepared by the method of Example 1 (reaction performed at room temperature) using 5-bromo-3-methoxy-2-pyrazinamine (0.15 g) and 3,4-dichlorobenzenesulphonyl chloride (0.15 g). Yield 0.09 g.