Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:38])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([F:17])=[CH:14][CH:15]=2)[C:10]([C:18]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[S:21](=[O:29])(=[O:28])[N:20]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[N:19]=2)=[C:9]1[CH3:37])(C)(C)C.C(O)(C(F)(F)F)=O>>[CH2:30]([N:20]1[N:19]=[C:18]([C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=3)[N:8]([CH2:7][C:6]([OH:38])=[O:5])[C:9]=2[CH3:37])[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[S:21]1(=[O:29])=[O:28])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: Cc1c(C2=NN(Cc3ccccc3)S(=O)(=O)c3ccccc32)c2cc(F)ccc2n1CC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(C2=NN(Cc3ccccc3)S(=O)(=O)c3ccccc32)c2cc(F)ccc2n1CC(=O)O

Procedure:
{[3-(2-Benzyl-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2,3]thiadiazin-4-yl)-5-fluoro-2-methyl-indol-1-yl]-acetic acid tert-butyl ester (61 μmol) was treated with TFA (2 mL) for 2 hours, concentrated, and purified by preparative LCMS to give the title compound. 1H NMR (d6-DMSO) δ 8.14 (d, 1H), 7.92 (t, 1H), 7.81 (t, 1H), 7.46 (d, 1H), 7.38 (m, 6H), 6.88 (dt, 1H), 6.61 (dd, 1H), 4.96 (s, 2H), 4.49 (s, 2H), 2.08 (s, 3H) ppm. MS calculated for C25H20FN3O4S—H: 476, observed: 476.
Reaction SMILES: [CH:1]1([C:6](Cl)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].[CH:11]1[C:23]2[CH:22]([CH2:24][O:25][C:26]([NH:28][C@@H:29]([CH2:33][CH2:34][NH2:35])[C:30]([OH:32])=[O:31])=[O:27])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]=2[CH:14]=[CH:13][CH:12]=1>C1COCC1>[CH:20]1[C:21]2[CH:22]([CH2:24][O:25][C:26]([NH:28][C@@H:29]([CH2:33][CH2:34][NH:35][C:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:7])[C:30]([OH:32])=[O:31])=[O:27])[C:23]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:16]=2[CH:17]=[CH:18][CH:19]=1
Reactant: O=C(Cl)C1CCCC1
Reactant: NCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(N[C@@H](CCNC(=O)C1CCCC1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Cyclopentanecarbonyl chloride (78 mg, 0.588 mmol) and NaOH (0.705 mL, 0.705 mmol) were dropped at the same time to a stirred solution of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-aminobutanoic acid (200 mg, 0.588 mmol) in THF (1.5 mL) and of NaOH (1N, 0.7 mL) at 0° C. The reaction mixture was allowed to stir at rt for 1 h at which time LC-MS showed desired product peak. The reaction solution was acidified with 1N HCl and extracted with EtOAc (60 mL×1). The crude materials were purified via flash chromatography (ISCO, silica gel, 12 g column; flow rate 30 mL/min, 100% DCM to 20% MeOH/DCM). Fractions containing the desired product were combined and dried via centrifugal evaporation to provide the title compound (84.1 mg, 33%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[Cl:8].[CH:9]1([B-](F)(F)F)[CH2:11][CH2:10]1.[K+].C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(P(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2)CCC>[Cl:8][C:7]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[CH:9]1[CH2:11][CH2:10]1
Reactant: Clc1ccncc1Br
Reactant: F[B-](F)(F)C1CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCCP(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2
Solvent: O
Solvent: Cc1ccccc1
Product: Clc1ccncc1C1CC1
Temperature: 115 °C
Reaction time: 8 h
Yield: 74.8 %

Procedure:
To a solution of 3-bromo-4-chloropyridine (CAN 36953-42-1, 4 g, 20.8 mmol) in a mixture of toluene (72 ml) and water (8.5 ml) under an argon atmosphere were added potassium cyclopropyltrifluoroborate (3.23 g, 21.8 mmol), palladium (II) acetate (93.3 mg, 416 μmol), butyldi-1-adamantylphosphine (224 mg, 624 μmol) and cesium carbonate (16.9 g, 52.0 mmol). The reaction mixture was stirred overnight at 115° C., cooled down to room temperature and filtered through a pad of celite. The filtrate was poured into a separatory funnel, diluted with ethyl acetate and extracted with an aqueous solution 1.0M sodium bicarbonate. The organic phase was collected, dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a heptane/(solution 3% triethylamine in ethyl acetate) gradient to yield the title product (2.39 g, 75%) as a yellow liquid. MS (ESI, m/z): 154.0 (M+H+).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)=[CH:9][C:8]([CH3:21])=[C:7]([C:22]([N:24]2[CH2:29][CH2:28][CH:27]([N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)[CH2:26][CH2:25]2)=[O:23])[N:6]=1)=[O:4].[OH-].[Li+]>C1COCC1.CO>[CH3:21][C:8]1[CH:9]=[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:19])([F:18])[F:20])[CH:12]=2)[C:5]([C:3]([OH:4])=[O:2])=[N:6][C:7]=1[C:22]([N:24]1[CH2:25][CH2:26][CH:27]([N:30]2[CH2:31][CH2:32][CH2:33][CH2:34]2)[CH2:28][CH2:29]1)=[O:23]
Reactant: COC(=O)c1nc(C(=O)N2CCC(N3CCCC3)CC2)c(C)cc1-c1cccc(C(F)(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)c(C(=O)O)nc1C(=O)N1CCC(N2CCCC2)CC1
Temperature: 25 °C
Reaction time: 28 h
Yield: 61.7 %

Procedure:
To a solution of 0.315 g (0.66 mmol) of 5-methyl-6-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-3-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic acid methyl ester (example 45) in 10 ml of THF/MeOH 1:1 were added 1.32 ml of lithium hydroxide (1 molar in H2O) and the reaction mixture was stirred at RT for 28 hours. Then, the solvents were evaporated and the residue was dissolved in H2O/CH2Cl2, neutralized with the help of hydrochloric acid and solid NaHCO3 and then extracted four times with CH2Cl2/2-propanol 3:1; the organic phases were dried over magnesium sulfate, filtered and evaporated, to give 0.188 g (62%) of the title compound as off-white solid. MS: 462.3 (MH+).
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]3([CH:20]=O)[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH:11]=[CH:10][C:9]=2[NH:22][C:23]([C:25]2[NH:26][CH:27]=[C:28]([C:30]#[N:31])[N:29]=2)=[O:24])=[CH:4][CH2:3]1.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CCOC(C)=O.C(Cl)Cl>CO.C(Cl)Cl>[CH3:1][C:2]1([CH3:32])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]3([CH2:20][N:33]4[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH:11]=[CH:10][C:9]=2[NH:22][C:23]([C:25]2[NH:26][CH:27]=[C:28]([C:30]#[N:31])[N:29]=2)=[O:24])=[CH:4][CH2:3]1
Reactant: C1COCCN1
Reactant: CC1(C)CC=C(c2cc(C3(C=O)CCOCC3)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: ClCCl
Product: CC1(C)CC=C(c2cc(C3(CN4CCOCC4)CCOCC3)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Yield: 43 %

Procedure:
The title compound was prepared by the procedure of Example 21, step (b) using 4-cyano-1H-imidazole-2-carboxylic acid [2-(4,4-dimethyl-cyclohex-1-enyl)-4-(4-formyl-tetrahydro-pyran-4-yl)-phenyl]-amide (as prepared in the previous step, 40.0 mg, 0.0921 mmol), morpholine (13 μL, 0.14 mmol) and sodium triacetoxyborohydride (5.2 mg, 0.14 mmol). Silica gel chromatography (10-20% EtOAc/DCM then 1-2% MeOH/DCM) afforded the title compound (20 mg, 43%) as a white solid. 1H-NMR (CDCl3; 400 MHz): δ 12.61 (s, 1H), 9.70 (s, 1H), 8.33 (d, 1H, J=8.6 Hz), 7.75 (s, 1H), 7.28 (dd, 1H, J=8.6, 2.3 Hz), 7.16 (d, 1H, J=2.3 Hz), 5.78 (m, 1H), 3.79 (m, 2H), 3.59 (m, 2H), 3.50-3.62 (m, 4H), 2.45 (s, 2H), 2.25-2.31 (m, 2H), 2.11-2.22 (m, 8H), 1.93 (m, 2H), 1.61 (t, 2H, J=6.3 Hz), 1.13 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C29H37N5O3, 504.3 (M+H). found 504.3.
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]2[C:15]([CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:16][CH:17]=[C:18]([Cl:19])[C:4]=2[N:3]=1.[CH3:25][C:26]1[C:30]([NH2:31])=[C:29]([CH3:32])[O:28][N:27]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN1CCCC1=O.C(OCC)(=O)C>[Cl:19][C:18]1[C:4]2[N:3]=[C:2]([NH:31][C:30]3[C:26]([CH3:25])=[N:27][O:28][C:29]=3[CH3:32])[N:6]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]=2[C:15]([CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:16][CH:17]=1
Reactant: Cc1noc(C)c1N
Reactant: CCOC(=O)CCCn1c(Cl)nc2c(Cl)ccc(C(CC)CC)c21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCn1c(Nc2c(C)noc2C)nc2c(Cl)ccc(C(CC)CC)c21
Temperature: 130 °C
Reaction time: 16 h
Yield: 50 %

Procedure:
A mixture of ethyl 4-[2,4-dichloro-7-(1-ethylpropyl)-1H-benzimidazol-1-yl]butanoate (Reference Example 33; 740 mg, 2.0 mmol), 3,5-dimethylisoxazol-4-amine (672 mg, 6.0 mmol) and p-toluenesulfonic acid monohydrate (380 mg, 2.0 mmol) in 1-methyl-2-pyrrolidinone (3 mL) was stirred at 130° C. for 16 hr. After cooling, the mixture was diluted with ethyl acetate, washed with aqueous sodium bicarbonate and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 20-60% ethyl acetate/n-hexane gradient mixture followed by recrystallization from ethyl acetate/n-hexane to give the title compound (450 mg, 1.0 mmol, 50%) as a colorless solid.
Reaction SMILES: [NH:1]([C:8]([CH3:15])=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.[C:21](OCC)(=[O:26])[C:22]#[C:23][CH2:24][CH3:25]>>[CH2:13]([O:12][C:10]([C:9]1[C:23]([CH2:24][CH3:25])=[CH:22][C:21](=[O:26])[N:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:8]=1[CH3:15])=[O:11])[CH3:14]
Reactant: CCOC(=O)C=C(C)Nc1ccccc1
Reactant: CCC#CC(=O)OCC
Solvent: C1CCOC1
Product: CCOC(=O)c1c(CC)cc(=O)n(-c2ccccc2)c1C

Procedure:
To a stirred solution of ethyl 3-anilinobut-2-enoate (50 mg, 0.2 mmol) in tetrahydrofuran (1 mL, 10 mmol) sodium hydride (60% NaH in mineral oil, 9.7 mg) was added. After 15 min ethyl 2-pentynoate (0.039 mL, 0.292 mmol) was added. After 60 min it was partitioned between ether (9 mL) and sat. aq. NaHCO3 (3 mL). The organic phase was washed twice with sat. aq. NaHCO3, dried (MgSO4) and evaporated. LC-MS (m/z) 286.3 (MH+); tR=1.27 (method C). 1H NMR (500 MHz, DMSO-d6): 1.13 (t, J=7.4 Hz, 3H, Me of Et), 1.28 (t, J=7.1 Hz, 3H, Me of EtO), 1.89 (s, 3H, 2-Me), 2.49 (q (overlapping with DMSO), J=7.4 Hz, 2H, CH2 of Et), 4.28 (q, J=7.1 Hz, 2H, CH2 of EtO), 6.28 (s, 1H, C5-H), 7.27 (t, J=7.3 Hz, 2H, two ortho-H of Ph), 7.47 (t, J=7.3 Hz, 1H, para-H of Ph), 7.53 (t, J=7.5 Hz, 2H, two meta-H of Ph).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[S:10][C:9]([NH:11][C:12]([N:14]2[C:30]3[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=3)[C:16]3([CH2:20][CH2:19][N:18]([C:21]([O:23][CH3:24])=[O:22])[CH2:17]3)[CH2:15]2)=[O:13])=[N:8][CH:7]=1.[CH:32]1([C:35](Cl)=[O:36])[CH2:34][CH2:33]1>>[Cl:31][C:27]1[CH:26]=[C:25]2[C:16]3([CH2:20][CH2:19][N:18]([C:21]([O:23][CH3:24])=[O:22])[CH2:17]3)[CH2:15][N:14]([C:12](=[O:13])[NH:11][C:9]3[S:10][C:6]([S:5][CH2:4][CH2:3][CH2:2][NH:1][C:35]([CH:32]4[CH2:34][CH2:33]4)=[O:36])=[CH:7][N:8]=3)[C:30]2=[CH:29][CH:28]=1
Reactant: O=C(Cl)C1CC1
Reactant: COC(=O)N1CCC2(C1)CN(C(=O)Nc1ncc(SCCCN)s1)c1ccc(Cl)cc12
Product: COC(=O)N1CCC2(C1)CN(C(=O)Nc1ncc(SCCCNC(=O)C3CC3)s1)c1ccc(Cl)cc12

Procedure:
The captioned compound was obtained in the form of a white solid by performing the same reactions and/or treatments as those in Example 3, with the exceptions that methyl 1-((5-((3-aminopropyl)thio)thiazol-2-yl)carbamoyl)-5-chlorospiro[indoline-3,3′-pyrrolidine]-1′-carboxylate was used instead of 5-bromo-N-(5-chlorothiazol-2-yl)spiro[indoline-3,3′-pyrrolidine]-1-carboxamide, and that cyclopropanecarbonyl chloride was used instead of acetyl chloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][O:8][C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15]([OH:17])=O)[CH:10]=2)=[CH:5][CH:4]=1.CN(C(ON1N=NC2C=CC(=CC1=2)Cl)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN(C=O)C.CCN(C(C)C)C(C)C.C([O:61][C:62](=[O:82])[C@H:63]([OH:81])[CH2:64][C@H:65]([NH2:80])[CH2:66][C:67]1[CH:72]=[CH:71][C:70]([C:73]2[CH:78]=[CH:77][CH:76]=[C:75]([Cl:79])[CH:74]=2)=[CH:69][CH:68]=1)C.CCO.[Li+].[OH-].O>>[Cl:79][C:75]1[CH:74]=[C:73]([C:70]2[CH:69]=[CH:68][C:67]([CH2:66][C@@H:65]([NH:80][C:15]([C:11]3[CH:10]=[C:9]([O:8][CH2:7][C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:19][CH:18]=4)[N:13]([CH3:14])[N:12]=3)=[O:17])[CH2:64][C@@H:63]([OH:81])[C:62]([OH:82])=[O:61])=[CH:72][CH:71]=2)[CH:78]=[CH:77][CH:76]=1
Reactant: COc1ccc(COc2cc(C(=O)O)nn2C)cc1
Reactant: CCOC(=O)[C@H](O)C[C@H](N)Cc1ccc(-c2cccc(Cl)c2)cc1
Agent: CN(C)C(On1nnc2ccc(Cl)cc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Li+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Solvent: CN(C)C=O
Product: COc1ccc(COc2cc(C(=O)N[C@H](Cc3ccc(-c4cccc(Cl)c4)cc3)C[C@@H](O)C(=O)O)nn2C)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 70.5 %

Procedure:
5-(4-Methoxy-benzyloxy)-1-methyl-1H-pyrazole-3-carboxylic acid (118.8 mg, 453 mol) was combined with HCTU (187.3 mg, 453 μmol) and DMF (2.0 mL, 25.9 mmol). The mixture was stirred at room temperature for 15 minutes. DIPEA (225 μL, 1.3 mmol) and (2R,4R)-4-amino-5-(3′-chlorobiphenyl-4-yl)-2-hydroxypentanoic acid ethyl ester (150 mg, 430 μmol) were added and the mixture was stirred at room temperature for 15 minutes. The solvent was removed in vacuo. EtOH (1.5 mL, 25.9 mmol) was added, followed by a solution of 1 M LiOH in water (4.3 mL, 4.3 mmol). The mixture was stirred at room temperature for 1 hour. The solvent was removed in vacuo and the product was purified by reverse phase chromatography to yield the title compound (171 mg).
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:10])[CH2:4][CH:5]([O:8][CH3:9])[O:6][CH3:7].[F:11][C:12]1[CH:13]=[CH:14][C:15]([C:18](O)=O)=[N:16][CH:17]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.O>CN(C=O)C>[CH3:7][O:6][CH:5]([O:8][CH3:9])[CH2:4][C:3]1[N:10]=[C:18]([C:15]2[CH:14]=[CH:13][C:12]([F:11])=[CH:17][N:16]=2)[O:1][N:2]=1
Reactant: COC(CC(=N)NO)OC
Reactant: O=C(O)c1ccc(F)cn1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: COC(Cc1noc(-c2ccc(F)cn2)n1)OC
Temperature: 40 °C
Reaction time: 1 h

Procedure:
A solution of N-hydroxy-3,3-dimethoxypropanimidamide obtained in Reference Example 19 (1.0 g, 6.8 mmol) in DMF (3 mL) was added to a solution of 5-fluoropyridine-2-carboxylic acid (1.0 g, 7.1 mmol) and carbonyldiimidazole (1.3 g, 8.1 mmol) in DMF (4 mL), which was stirred for 1 hour at 40° C., and the mixture was stirred for 30 minutes. The reaction solution was heated to 90° C. and stirred for 15 hours. Water was added to the reaction mixture, followed by extraction with EtOAc. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over Na2SO4, then the drying agent was filtered off, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 25 g, hexane/EtOAc=75/25 to 0/100) to obtain the title compound (1.2 g) (colorless solid).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([O:10][CH3:11])[C:3]=1[S:12][CH3:13].[CH3:14][OH:15].[OH-].[K+]>O>[CH3:13][S:12][C:3]1[C:4]([O:10][CH3:11])=[N:5][C:6]([O:8][CH3:9])=[N:7][C:2]=1[O:15][CH3:14]
Reactant: CO
Reactant: COc1nc(Cl)c(SC)c(OC)n1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COc1nc(OC)c(SC)c(OC)n1

Procedure:
Charged into a 100-milliliter, 4-necked flask equipped with a reflux condenser, thermometer and stirrer were 2.2 g of 6-chloro-2,4-dimethoxy-5-methylthiopyrimidine and 40 ml of methanol. They were stirred into a homogeneous solution. Subsequent to an addition of 2.0 g of potassium hydroxide, the resultant mixture was heated and refluxed, with thorough stirring, for 3 hours. The liquid reaction mixture was then poured into water and the resultant solid precipitate was collected by filtration. It was recrystallized from isopropyl alcohol, thereby obtaining 5-methylthio-2,4,6-trimethoxypyrimidine (m.p. 90°-91° C.). Yield: 1.96 g(90.7%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([CH2:15][NH:16][C:17]([C:19]2[CH:20]=[N:21][N:22]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([CH2:31][N:32]4[C:36](=[O:37])[CH2:35][CH2:34][C:33]4=[O:38])=[CH:27][CH:26]=3)[CH:23]=2)=[O:18])=[C:10]([CH3:39])[N:9]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C:8]1[N:9]=[C:10]([CH3:39])[C:11]([CH2:15][NH:16][C:17]([C:19]2[CH:20]=[N:21][N:22]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([CH2:31][N:32]4[C:33](=[O:38])[CH2:34][CH2:35][C:36]4=[O:37])=[CH:27][CH:26]=3)[CH:23]=2)=[O:18])=[C:12]([CH3:14])[CH:13]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CNC(=O)c1cnn(Cc2ccc(CN3C(=O)CCC3=O)cc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(N)nc(C)c1CNC(=O)c1cnn(Cc2ccc(CN3C(=O)CCC3=O)cc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of {5-[({1-[4-(2,5-Dioxo-pyrrolidin-1-ylmethyl)-benzyl]-1H-pyrazole-4-carbonyl}-amino)-methyl]-4,6-dimethyl-pyridin-2-yl]-carbamic acid tert-butyl ester (48 mg, 0.08 mmol), 1 mL TFA and 2 mL DCM was stirred of room temperature for 2 h. The mixture was evaporated in vacuo and the residue was purified by preparative HPLC (Macherey-Nagel Nucleosil 250×40 mm, 5 to 100% ACN and 0.1% TFA, flow 40ml/min). The product containing fractions were lyophilised, then dissolved in 1 mL MeOH and the resulting mixture was filtered over a MeOH flushed PL-HCO3 MP-resin column. The column was washed with MeOH, the solvent was removed and the product was dissolved in water/ACN and lyophilised to yield the title compound. 1H-NMR (DMSO-d6, 400 MHz) 88.25 (s, 1H), 7.91 (t, 1H), 7.87 (s, 1H), 7.24 (d, 2H), 7.20 (d, 2H), 6.13 (s, 1H), 5.70 (bs, 2H), 5.28 (s, 2H), 4.52 (d, 2H), 2.67 (s, 4H), 2.29 (s, 3H), 2.15 (s, 3H); LCMS (method A) RtA=0.439 min; [M+H]+=447.1.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[O:13][C:14]4[CH:26]=[CH:25][CH:24]=[CH:23][C:15]=4[C:16]=3[C:17](=[O:22])[CH2:18][CH2:19][CH2:20][CH3:21])=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:27][CH2:28][C:29]#[N:30].[N-:31]=[N+:32]=[N-:33].[Na+].[Cl-].[NH4+].Cl>CN(C=O)C.O>[Br:1][C:2]1[C:3]([O:27][CH2:28][C:29]2[NH:33][N:32]=[N:31][N:30]=2)=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[CH:9][C:8]([C:12]1[O:13][C:14]3[CH:26]=[CH:25][CH:24]=[CH:23][C:15]=3[C:16]=1[C:17](=[O:22])[CH2:18][CH2:19][CH2:20][CH3:21])=[CH:7]2
Reactant: CCCCC(=O)c1c(-c2ccc3c(Br)c(OCC#N)ccc3c2)oc2ccccc12
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCC(=O)c1c(-c2ccc3c(Br)c(OCc4nnn[nH]4)ccc3c2)oc2ccccc12
Temperature: 80 °C
Yield: 43.3 %

Procedure:
A mixture of 2-{[1-bromo-6-(3-pentanoyl-1-benzofuran-2-yl)-2-naphthyl]oxy}acetonitrile (0.488 g, 1.06 mmol), sodium azide (0.347 g, 5.34 mmol), ammonium chloride (0.289 g, 5.40 mmol) in DMF (10 ml) was heated to 80° C. for 2 hours. The reaction mixture was allowed to cool to room temperature. It was poured into excess water, acidified with 2N hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water and brine. It was dried over anhydrous magnesium sulfate, filtered and solvent evaporated. The residue was purified by HPLC using 0.1% TFA in 80% acetonitrile/20% water as the mobile phase. The acetonitrile was evaporated and the residue was extracted with ethyl acetate The extract was washed with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The solid was dried at 90° C. for 11 hours affording the title compound as a light yellow solid (0.232 g), m184-185° C. Mass spectrum (+APCl, [M+H]+) m/z 505. 1HNMR (400 MHz, DMSO-d6): δ16.8-17.2 (br s, 1H), 8.5 (d, 1H, J=1.7 Hz), 8.25 (t, 2H, J=9.1 Hz), 8.0-8.05 (m, 2H), 7.75-7.8 (m, 2H), 7.4-7.5 (m, 2H), 5.8 (s, 2H), 2.75 (t, 2H, J=7.3 Hz), 1.5-1.6 (m, 2H), 1.1-1.2 (m, 2H), and 0.7 ppm (t, 3H, J=7.3 Hz). Elemental Analysis for C25H21, BrN4O3: Calculated: C, 59.42; H, 4.19; N, 11.09. Found: C, 59.03; H, 3.98; N, 10.75.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:28]=[CH:27][C:16]([C:17]([O:19]CC3C=CC=CC=3)=[O:18])=[CH:15][C:14]=2[O:29][CH3:30])[N:3]=1>C1COCC1.[OH-].[OH-].[Pd+2]>[Cl:1][C:2]1[C:7]([C:8]([F:10])([F:9])[F:11])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:28]=[CH:27][C:16]([C:17]([OH:19])=[O:18])=[CH:15][C:14]=2[O:29][CH3:30])[N:3]=1
Reactant: COc1cc(C(=O)OCc2ccccc2)ccc1Nc1ncc(C(F)(F)F)c(Cl)n1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc(C(=O)O)ccc1Nc1ncc(C(F)(F)F)c(Cl)n1
Reaction time: 24 h

Procedure:
Benzyl 4-(4-chloro-5-trifluoromethyl-pyrimidin-2-ylamino)-3-methoxy-benzoate (A3-a) (1.3 g, 3 mmol) is suspended in a hydrogenating autoclave in 50 mL THF and mixed with Pd(OH)2 on charcoal (180 mg, charge 20%, approx. 50% water). Then 4.5 bar H2 pressure are applied and the reaction mixture is stirred for 24 h. After the reaction has ended the reaction mixture is filtered, the filtrate is evaporated down and the crude product A-4a (HPLC-MS: tRet.=1.24 min; MS (M−H)+=346) is used in the subsequent reactions without any further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:38])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](Cl)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([C:33]#[N:34])([CH3:32])[CH3:31])=[CH:26][C:25]=3[O:35][CH2:36][CH3:37])=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl.[N:41]1([CH2:47][CH2:48][NH:49][C:50](=[O:52])[CH3:51])[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([CH3:38])[C@:12]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)([CH3:13])[N:11]([C:21]([N:44]3[CH2:45][CH2:46][N:41]([CH2:47][CH2:48][NH:49][C:50](=[O:52])[CH3:51])[CH2:42][CH2:43]3)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([C:33]#[N:34])([CH3:32])[CH3:31])=[CH:26][C:25]=3[O:35][CH2:36][CH3:37])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC(=O)NCCN1CCNCC1
Reactant: CCOc1cc(C(C)(C)C#N)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Agent: Cl
Product: CCOc1cc(C(C)(C)C#N)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCNC(C)=O)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-[4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with N-(2-piperazin-1-yl-ethyl)-acetamide dihydrochloride (prepared as described in Fotouhi, N. et al. WO 2005110996) to give the title compound as a racemic mixture. The enantiomers were then separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 35% methanol in carbon dioxide). LR-MS: 703.3 [(M+H)+]
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][C:11]([F:14])([F:13])[F:12].[F:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=1B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1COCC1.CN(C=O)C>[F:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=1[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][C:11]([F:14])([F:13])[F:12]
Reactant: O=Cc1ccc(Cl)c(OC(F)(F)F)c1
Reactant: COc1ccc(F)c(B(O)O)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(F)c(-c2ccc(C=O)cc2OC(F)(F)F)c1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
A screw-cap vial was charged with 4-chloro-3-(trifluoromethoxy)benzaldehyde (available from Alfa Aesar, Avocado, Lancaster) (0.184 g, 0.82 mmol), 2-fluoro-5-methoxyphenylboronic acid (available from Aldrich) (0.278 g, 1.64 mmol), potassium phosphate (0.522 g, 2.46 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (0.101 g, 0.25 mmol), palladium(II) acetate (0.018 g, 0.082 mmol), and 5:1 THF/DMF (3.6 mL). The mixture was stirred overnight at 40° C., cooled to room temperature, diluted with EtOAc, washed with water and brine, dried (MgSO4), and concentrated. The residue was chromatographed on silica gel (0-10% EtOAc/hexane) to afford K.1 (165 mg, 64%) as a colorless oil.