Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:7][C:8]1[N:9]=[C:10]([OH:58])[C:11]2[CH:17]=[C:16]([C:18]#[C:19][C:20]3[N:21](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:22]=[C:23]([C:25]([NH:27][C@H:28]([C:35]([O:37][CH3:38])=[O:36])[CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[O:26])[N:24]=3)[CH:15]=[N:14][C:12]=2[N:13]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[H][H]>[Pd].CO>[C:1]([NH:7][C:8]1[N:9]=[C:10]([OH:58])[C:11]2[CH2:17][CH:16]([CH2:18][CH2:19][C:20]3[NH:21][CH:22]=[C:23]([C:25]([NH:27][C@H:28]([C:35]([O:37][CH3:38])=[O:36])[CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[O:26])[N:24]=3)[CH2:15][NH:14][C:12]=2[N:13]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: [H][H]
Reactant: COC(=O)CC[C@H](NC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(C#Cc2cnc3nc(NC(=O)C(C)(C)C)nc(O)c3c2)n1)C(=O)OC
Agent: [Pd]
Solvent: CO
Product: COC(=O)CC[C@H](NC(=O)c1c[nH]c(CCC2CNc3nc(NC(=O)C(C)(C)C)nc(O)c3C2)n1)C(=O)OC
Yield: 47.7 %

Procedure:
A mixture of dimethyl N-{2-[2-(2-pivaloylamino-4-hydroxypyrido[2,3-d]-pyrimidin-6-yl)ethynyl]-1-triphenylmethylimidazol-4-ylcarbonyl}-L-glutamate (390 mg, 0.5 mmol) and 10% palladium-on-carbon catalyst (390 mg) in methanol (15 mL) was stirred under 50 psi of hydrogen for 7 days at room temperature. The workup was performed as described in Example 2 to yield 130 mg (48%) of dimethyl N-{2-[2-(2-pivaloylamino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl)ethyl]imidazol-4-ylcarbonyl}-L-glutamate as a pale yellow solid, mp 129-131° C.: 1H NMR (CDCl3) δ 11.35 (br s, 1H), 8.95 (br s, 1H), 7.54 (d, 1H, J=8.4 Hz), 7.49 (s, 1H), 4.75 (m, 1H), 3.69 (s, 3H), 3.60 (s, 3H), 3.30 (M, 1H), 2.87 (m, 1H), 2.80-2.60 (m, 3H), 2.43 (m, 2H), 2.27 (m, 1H), 2.15-1.92 (m, 2H), 1.80-1.60 (m, 3H), 1.26 (s, 9H).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:5]=[CH:4][N:3]=1.[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([OH:28])=[CH:20][N:19]=1>>[F:15][C:14]([F:17])([F:16])[C:11]1[CH:12]=[CH:13][C:8]([C:6]2[N:5]=[CH:4][N:3]=[C:2]([O:28][C:21]3[C:22]4[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:18]=[N:19][CH:20]=3)[CH:7]=2)=[CH:9][CH:10]=1
Reactant: Fc1cc(-c2ccc(C(F)(F)F)cc2)ncn1
Reactant: Oc1cncc2ccccc12
Product: FC(F)(F)c1ccc(-c2cc(Oc3cncc4ccccc34)ncn2)cc1

Procedure:
The title compound was prepared from 4-fluoro-6-(4-trifluoromethyl-phenyl)-pyrimidine (Example 169(a) and isoquinolin-4-ol (MonomerChem) analogous to the conditions described in Example 169(b). Mp: 206-211° C. MS (ESI, pos. ion) m/z: 368.2 (M+1).
Reaction SMILES: [C:1]([NH:11][C:12]1([C:15]([OH:17])=[O:16])[CH2:14][CH2:13]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C1(N=C=NC2CCCCC2)CCCCC1.CN(C1C=CC=CN=1)C.[CH3:42][C:43]1([CH3:51])[CH2:47][CH2:46][C:45]([CH3:49])([CH3:48])[CH:44]1O>C(Cl)Cl>[CH3:42][C:43]1([CH3:51])[CH2:47][CH2:46][C:45]([CH3:49])([CH3:48])[CH:44]1[O:16][C:15]([C:12]1([NH:11][C:1]([O:3][CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:2])[CH2:14][CH2:13]1)=[O:17]
Reactant: CC1(C)CCC(C)(C)C1O
Reactant: O=C(NC1(C(=O)O)CC1)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: CC1(C)CCC(C)(C)C1OC(=O)C1(NC(=O)OCc2ccccc2)CC1
Reaction time: 96 h

Procedure:
To a stirred solution of N-Cbz-1aminocyclopropane carboxylic acid in dry (CH2)2Cl2 containing dicyclohexylcarbodiimide and dimethylaminopyridine (DMAP), all at 0° C., is added, via an addition funnel, 2,2,5,5-tetramethylcyclopentanol dissolved in CH2Cl2. After stirring for 4 days, the mixture is filtered, and the filtrate is washed with 5% HCl (1×50 ml), saturated NaHCO3 (1×50 ml), and water (1×50 ml). The organic layer is separated, dried over MgSO4 and evaporated to yield N-Cbz-1-aminocyclopropanecarboxylic acid 2,2,5,5-tetramethylcyclopentyl ester.
Reaction SMILES: Br[C:2]1[CH:18]=[CH:17][C:5]([O:6][CH:7]([CH3:16])[CH2:8][NH:9][S:10]([CH:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])=[CH:4][CH:3]=1.[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.COCCOC>[CH3:14][CH:13]([S:10]([NH:9][CH2:8][CH:7]([O:6][C:5]1[CH:17]=[CH:18][C:2]([C:2]2[CH:18]=[CH:17][C:5]([C:20]3[S:19][CH:23]=[CH:22][CH:21]=3)=[CH:4][CH:3]=2)=[CH:3][CH:4]=1)[CH3:16])(=[O:12])=[O:11])[CH3:15]
Reactant: OB(O)c1cccs1
Reactant: CC(CNS(=O)(=O)C(C)C)Oc1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(CNS(=O)(=O)C(C)C)Oc1ccc(-c2ccc(-c3cccs3)cc2)cc1
Yield: 88.6 %

Procedure:
The title compound (145 mg, 54%, yellow foam) was prepared from [2-(4-bromophenoxy)propyl][(methylethyl)sulfonyl]amine (265 mg, 0.788 mmol, prepared in example 1), 2-thienylboronic acid (125 mg, 0.946 mmol), dichlorobis(triphenylphosphine)palladium(II) (22 mg, 0.031 mmol), 2 M sodium carbonate (285 mg in 1.35 mL water), and 1,2-dimethoxyethane (5.25 mL) in a manner analogous to the procedure described in Example 8.
Reaction SMILES: [CH:1]1([C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[NH2:6])[CH2:3][CH2:2]1.[C:11]([N:19]=[C:20]=[S:21])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CC(C)=O>[CH:1]1([C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[NH:6][C:20]([NH:19][C:11](=[O:18])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[S:21])[CH2:3][CH2:2]1
Reactant: Nc1ccccc1C1CC1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: CC(C)=O
Product: O=C(NC(=S)Nc1ccccc1C1CC1)c1ccccc1
Temperature: 50 °C

Procedure:
To 2-cyclopropylaniline (498 mg, 3.74 mmol) in acetone (10 mL) was added benzoyl isothiocyanate (0.53 mL, 3.93 mmol) and the mixture was heated at 50° C. for 8 hours. The reaction mixture was concentrated to provide N-((2-cyclopropylphenyl)carbamothioyDbenzamide as a orange oil (1.249 g, 100%): 1H NMR (400 MHz, CDCl3) δ 12.59 (s, 1H), 9.14 (s, 1H), 8.07 (dd, J=7.8, 1.3 Hz, 1H), 7.92 (dd, J=8.4, 1.2 Hz, 2H), 7.69-7.63 (m, 1H), 7.59-7.52 (m, 2H), 7.31-7.26 (m, 1H), 7.23 (td, J=7.5, 1.5 Hz, 1H), 7.13 (dd, J=7.6, 1.5 Hz, 1H), 1.95 (qt, J=12.3, 4.4 Hz, 1H), 1.09-1.01 (m, 2H), 0.76-0.69 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 178.70, 166.72, 137.59, 137.06, 133.71, 131.72, 129.22, 127.51, 127.20, 126.93, 126.12, 125.26, 11.72, 7.03; ESIMS m/z 295 ([M−H]−).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:11]([CH2:19][C:20]([OH:22])=[O:21])[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+].[CH2:33](O)[CH3:34]>>[CH2:33]([O:21][C:20](=[O:22])[CH2:19][C:11]1[CH:10]=[N:9][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:34]
Reactant: CCO
Reactant: O=C(O)Cc1cnn(Cc2ccccc2)c1-c1ccccc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)Cc1cnn(Cc2ccccc2)c1-c1ccccc1
Yield: 89 %

Procedure:
A mixture of (1-benzyl-5-phenyl-1H-pyrazol-4-yl)acetic acid (3.70 g), concentrated sulfuric acid (0.5 ml), and ethanol (200 ml) was refluxed for 5 hours. The reaction mixture was alkalinized with saturated aqueous sodium bicarbonate, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography, and ethyl(1-benzyl-5-phenyl-1H-pyrazol-4-yl)acetate (3.62 g, yield: 89%) was obtained as an oily substance from the fraction eluted with ethyl acetate-hexane (1:6, volume ratio).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[S:21]1[CH2:25][CH:24]([C:26]([NH2:28])=[O:27])[NH:23][CH2:22]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:23]3[CH:24]([C:26]([NH2:28])=[O:27])[CH2:25][S:21][CH2:22]3)=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: NC(=O)C1CSCN1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)C1CSCN1C(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with and 4-thiazolidinecarboxamide (CAN 103749-87-7) in the presence of TBTU and DIEA to obtain the title compound as white solid; MS (EI): m/e=399.5 [MH+].
Reaction SMILES: CC(O)=O.CCO.[Cl:8][C:9]1[C:25]([F:26])=[CH:24][CH:23]=[C:22]([Cl:27])[C:10]=1[CH2:11][O:12][C:13]1[C:14]([N+:19]([O-])=O)=[N:15][CH:16]=[CH:17][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>[Fe].O.C(OCC)C>[Cl:8][C:9]1[C:25]([F:26])=[CH:24][CH:23]=[C:22]([Cl:27])[C:10]=1[CH2:11][O:12][C:13]1[C:14]([NH2:19])=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=[N+]([O-])c1ncccc1OCc1c(Cl)ccc(F)c1Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: CCOCC
Product: Nc1ncccc1OCc1c(Cl)ccc(F)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.4 %

Procedure:
To a stirred mixture of AcOH (650 mL) and EtOH (500 mL) was suspended 3-(2,6-dichloro-3-fluoro-benzyloxy)-2-nitro-pyridine (9.43 g, 0.028 mol) and iron chips (15.7 g, 0.28 mol). The reaction was heated slowly to reflux and allowed to stir for 1 hr. The reaction was cooled to room temperature then diethyl ether (500 mL) and water (500 mL) was added. The solution was carefully neutralized by the addition of sodium carbonate. The combined organic extracts were washed with sat'd NaHCO3 (2×100 mL), H2O (2×100 mL) and brine (1×100 mL) then dried (Na2SO4), filtered and concentrated to dryness under vacuum to yield 3-(2,6-dichloro-3-fluoro-benzyloxy)-pyridin-2-ylamine (9.04 g, 0.027 mol, 99%) as a light pink solid. 1H NMR (CDCl3, 300 MHz) 1.8-1.85 (d, 3H), 4.9-5.2 (brs, 2H), 6.7-6.84 (q, 1H), 7.0-7.1 (m, 1H), 7.2-7.3 (m, 1H), 7.6-7.7 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([OH:13])=O)[S:10][C:3]=12.[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)=[O:13])[S:10][C:3]=12
Reactant: C1CCNC1
Reactant: O=C(O)c1cc2nccc(Cl)c2s1
Product: O=C(c1cc2nccc(Cl)c2s1)N1CCCC1

Procedure:
This material was prepared from the coupling of 7-chlorothieno[3,2-b]pyridine-2-carboxylic acid and pyrrolidine in a manner as previously described for example 9d. 1H NMR (300 MHz, CD3OD) δ8.60 (1H, d, J=5.1 Hz), 7.84 (1H, s), 7.32 (1H, d, J=5.1 Hz), 3.82 (2H, t, J=6.4 Hz), 3.70 (2H, t, J=6.6 Hz), 2.02 (4H, m). LCMS (ESI+) [M+H]/z Calc'd 267, found 267.
Reaction SMILES: [NH2:1][C@@H:2]([C@H:38]([C:46]1[CH:54]=[CH:53][C:49]2[O:50][CH2:51][O:52][C:48]=2[CH:47]=1)[C:39]1[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=1)[C:3]([NH:5][C:6]1[CH:7]=[N:8][CH:9]=[C:10]([F:37])[C:11]=1[CH2:12][CH2:13][C@H:14]1[O:19][CH2:18][C@@H:17]([CH2:20][O:21][C:22](=[O:29])[NH:23][CH2:24][C:25]([F:28])([F:27])[F:26])[N:16]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:15]1)=[O:4].C(N(CC)CC)C.Cl[C:63]([O:65][CH3:66])=[O:64]>ClCCl>[O:50]1[C:49]2[CH:53]=[CH:54][C:46]([C@H:38]([C:39]3[CH:40]=[CH:41][C:42]([Cl:45])=[CH:43][CH:44]=3)[C@H:2]([NH:1][C:63]([O:65][CH3:66])=[O:64])[C:3]([NH:5][C:6]3[CH:7]=[N:8][CH:9]=[C:10]([F:37])[C:11]=3[CH2:12][CH2:13][C@H:14]3[O:19][CH2:18][C@@H:17]([CH2:20][O:21][C:22](=[O:29])[NH:23][CH2:24][C:25]([F:27])([F:26])[F:28])[N:16]([C:30]([O:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:31])[CH2:15]3)=[O:4])=[CH:47][C:48]=2[O:52][CH2:51]1
Reactant: COC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CCc2c(F)cncc2NC(=O)[C@@H](N)[C@@H](c2ccc(Cl)cc2)c2ccc3c(c2)OCO3)OC[C@H]1COC(=O)NCC(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)N[C@H](C(=O)Nc1cncc(F)c1CC[C@@H]1CN(C(=O)OC(C)(C)C)[C@H](COC(=O)NCC(F)(F)F)CO1)[C@@H](c1ccc(Cl)cc1)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a stirred solution of the product from step 3 (50 mg, 0.06 mmol) in dichloromethane (2 mL) was added triethylamine (0.02 mL, 0.13 mmol) and methyl chloroformate (0.006 mL, 0.07 mmol). The mixture was stirred at ambient temperature for 6 h, then diluted with dichloromethane (10 mL) and washed with aqueous NaHCO3 and brine. The organic phase was dried (MgSO4), filtered, and the solvents were removed in vacuo. The residue was chromatographed on a 12 g SiO2 column using a gradient elution of 0-100% EtOc in hexanes. Fractions containing product were combined and the solvents were removed in vacuo to give the title compound as a gum. (M+H)+=840.
Reaction SMILES: COC1C=CC(C=O)=CC=1.OC1C=C(C=O)C=CC=1C.OC1C=C(C=O)C(C)=CC=1.OC1C(C)=CC(C=O)=CC=1.[OH:41][C:42]1[CH:47]=[CH:46][C:45](C)=[CH:44][C:43]=1[CH:49]=[O:50]>>[OH:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[CH:49]=[O:50]
Reactant: Cc1ccc(O)c(C=O)c1
Agent: COc1ccc(C=O)cc1
Agent: Cc1cc(C=O)ccc1O
Agent: Cc1ccc(C=O)cc1O
Product: O=Cc1ccccc1O

Procedure:
p-methoxybenzaldehyde; 2-hydroxy-p-tolualdehyde; 4-hydroxy-o-tolualdehyde; 6-hydroxy-m-tolualdehyde; and 4-hydroxy-m-tolualdehyde.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][CH:3]([CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11](=[O:17])[NH:12][CH2:13][C:14](O)=[O:15])[S:2]1.[S:18]([NH2:22])([NH2:21])(=[O:20])=[O:19].[H-].[Na+]>CN(C)C=O>[S:1]1[CH2:5][CH2:4][CH:3]([CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11](=[O:17])[NH:12][CH2:13][C:14]([NH:21][S:18]([NH2:22])(=[O:20])=[O:19])=[O:15])[S:2]1
Reactant: NS(N)(=O)=O
Reactant: O=C(O)CNC(=O)NCCCCC1CCSS1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NS(=O)(=O)NC(=O)CNC(=O)NCCCCC1CCSS1
Yield: 29.7 %

Procedure:
The reaction was carried out as described in Example 73, but using 0.20 g of 3-[4-(1,2-dithiolan-3-yl)butyl]ureidoacetic acid (prepared as described in Example 48), 4 ml of anhydrous dimethylformamide, 0.13 g of N,N'-carbonyldiimidazole, 0.15 g of sulfamide and 0.04 g of sodium hydride (as a 55% w/w dispersion in mineral oil). The solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue. The mixture was neutralized by the addition of 2 N aqueous hydrochloric acid, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was recrystallized from a mixture of methanol and ethyl acetate, to obtain 76 mg of the title compound as yellow crystals, melting at 143 to 145° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[F:20])=[C:9](/[C@H:11]2[CH2:16][CH2:15][C@H:14]([CH2:17][CH2:18][CH3:19])[CH2:13][CH2:12]2)\[F:10])=[CH:4][CH:3]=1.Cl.[CH2:22]1[CH2:26]OC[CH2:23]1>>[CH2:23]([C@H:2]1[CH2:7][CH2:6][C@H:5](/[C:8](/[F:20])=[C:9](/[C@H:11]2[CH2:16][CH2:15][C@H:14]([CH2:17][CH2:18][CH3:19])[CH2:13][CH2:12]2)\[F:10])[CH2:4][CH2:3]1)[CH2:22][CH3:26]
Reactant: CCC[C@H]1CC[C@H](/C(F)=C(\F)c2ccc(F)cc2)CC1
Reactant: C1CCOC1
Agent: Cl
Product: CCC[C@H]1CC[C@H](/C(F)=C(\F)[C@H]2CC[C@H](CCC)CC2)CC1
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
Then, a mixed solution containing 1.3 g (6.31 mmol) of 2-(trans-4-n-propylcyclohexyl)-1,1,2-trifluoroethylene obtained in Example 1 and 10 ml of dry THF, was dropwise added thereto at the same temperature over a period of 15 minutes. The mixture was reacted at the same temperature for one hour and then the temperature was raised to -10° C. Then, 100 ml of 1N hydrochloric acid was added thereto. The organic layer was separated. The aqueous layer was extracted with n-hexane, and the extract was combined with the organic layer. The combined organic layer was washed with water and dried. Then, the solvent was distilled off, and the obtained crude solution was purified by silica gel column chromatography. The obtained solid was further recrystallized from ethanol to obtain 1.18 g (yield: 60%) of (E)-1,2-bis(trans-4-n-propylcyclohexyl)-1,2-difluoroethylene.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[CH:12]([O:15][C:16]1[NH:20][N:19]=[C:18]([NH2:21])[CH:17]=1)([CH3:14])[CH3:13].C(N(CC)CC)C>C(#N)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:21][C:18]2[CH:17]=[C:16]([O:15][CH:12]([CH3:14])[CH3:13])[NH:20][N:19]=2)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: CC(C)Oc1cc(N)n[nH]1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)Oc1cc(Nc2nc(Cl)ncc2[N+](=O)[O-])n[nH]1
Temperature: 25 °C
Reaction time: 24 h
Yield: 32.5 %

Procedure:
A mixture of 2,4-dichloro-5-nitropyrimidine (2 g) and 5-isopropoxy-1H-pyrazol-3-amine (Intermediate 6, 1.5 g) in acetonitrile (50 mL) with triethylamine (5 mL) was stirred at room temperature for 24 hours, The resulting mixture was concentrated, and the resulting residue was separated by silica gel column (Hexane/Ethyl acetate) to afford 1 g of the title compound. MS (electrospray): 299 (M+1) for C10H12ClN6O3.
Reaction SMILES: [O:1]=[C:2]1[CH2:5][CH:4]([C:6]([OH:8])=O)[CH2:3]1.[CH2:9]([NH2:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[CH2:9]([NH:16][C:6]([CH:4]1[CH2:3][C:2](=[O:1])[CH2:5]1)=[O:8])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NCc1ccccc1
Reactant: O=C1CC(C(=O)O)C1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1CC(C(=O)NCc2ccccc2)C1
Yield: 40.3 %

Procedure:
Acid, 3-oxocyclobutanecarboxylic acid (10 g, 0.087 mol), benzylamine (10.5 mL, 0.96 mol), and triethylamine (38 mL, 0.26 mol) were dissolved in DMF (100 mL). BOP (38.7 g, 0.087 mol) was added at 0° C. under stirring in argon. The mixture was stirred at 20° C. for 20 h, evaporated, and the residue was dried at 0.5 mmHg. The residue was purified by chromatography (silica gel, 63-100 μm, 1 L, CCl4→CHCl3, CHCl3/MeOH 100:0→95:5). The title compound (7.12 g, 40%) was obtained as a colorless oil. 1H NMR-data (DMSO-d6): 8.62 (br.s, 1H, NH); 7.21-7.36 (m, 5H, Ph); 4.32 (d, 2H, CH2, J=6.1 Hz); 3.10-3.28 (m, 5H).
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1[N:19]1[N:23]=[CH:22][CH:21]=[N:20]1)=[O:10].Cl[C:25]1[N:30]=[C:29]([CH3:31])[C:28]([F:32])=[CH:27][N:26]=1.CCN(C(C)C)C(C)C>C(#N)C>[F:32][C:28]1[C:29]([CH3:31])=[N:30][C:25]([N:7]2[CH2:8][CH:4]3[CH:5]([CH2:1][N:2]([C:9]([C:11]4[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=4[N:19]4[N:20]=[CH:21][CH:22]=[N:23]4)=[O:10])[CH2:3]3)[CH2:6]2)=[N:26][CH:27]=1
Reactant: COc1ccc(C(=O)N2CC3CNCC3C2)c(-n2nccn2)c1
Reactant: Cc1nc(Cl)ncc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1ccc(C(=O)N2CC3CN(c4ncc(F)c(C)n4)CC3C2)c(-n2nccn2)c1

Procedure:
(Hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone (Example 288-step B, 33 mg, 0.10 mmol), 2-chloro-5-fluoro-4-methylpyrimidine (Intermediate 55, 15 mg, 0.10 mmol) and DIPEA (54 μL, 0.3 mmol) in ACN (1 mL) were heated in a microwave reactor for 2 h at 200° C. Then the reaction mixture was concentrated and purified via prep HPLC (Agilent, basic) gave the title compound as a clear oil. MS (ESI) mass calcd. C21H22FN7O2, 423.45; m/z found 424.2 [M+H]+. 1H NMR (CDCl3): 8.06 (d, J=1.8 Hz, 1H), 7.74 (s, 2H), 7.50 (d, J=5.8 Hz, 1H), 7.33 (d, J=8.5 Hz, 1H), 6.95 (dd, J=8.5, 2.5 Hz, 1H), 3.93-3.76 (m, 5H), 3.71-3.59 (m, 2H), 3.53 (dd, J=11.4, 5.2 Hz, 1H), 3.44-3.30 (m, 2H), 3.07-2.87 (m, 3H), 2.37 (t, J=4.9 Hz, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2].[NH2:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=1.Cl>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2]
Reactant: Nc1ccc(C=O)cc1
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1Cl
Agent: Cl
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc2c(OC)cccc2c1Nc1ccc(C=O)cc1
Temperature: 90 °C
Yield: 57 %

Procedure:
4-Chloro-8-methoxy-3-quinolinecarboxylic acid ethyl ester (10.62 g, 40 mmol) and 4-aminobenzaldehyde (4.85 g, 40 mmol) were suspended in dry DMF (100 mL) and treated dropwise with concentrated HCl (aq) (3.3. mL, 40 mmol). The mixture was heated at 90° C. for 40 min. After dilution with methylene chloride (800 mL) the reaction mixture was extracted with 1N NaOH (200 mL) and water (3×200 mL) and the dried (MgSO4) organic phase evaporated to a yellow oil. Crystallization from a minimum amount of ether afforded 8.0 g (22.8 mmol), 57% yield) of the product as a light yellow solid: m.p. 108°-110° C. (dec): 1H NMR (Me2SO-d6, 400 MHz) δ 9.79 (s, 1 H), 9.70 (s, 1 H), 8.99 (s, 1 H), 7.75 (d, J=8.7 Hz, 2 H), 7.64 (d, J=7.9 Hz, 1 H), 7.52 (t, J=7.9 Hz, 1 H), 7.31 (d, J=7.9 Hz, 1 H), 7.01 (d, J=8.5 Hz, 2 H), 4.02 (q, J=7.1 Hz, 2 H), 3.99 (s, 3 H), 1.08 (t,J=7.1 Hz, 3 H); MS(EI), m/z (rel. intensity)=350 (M+, 100), 321(34), 275(68), 247(58), 218(35), 205(18), 190(21); IR(KBr) 3430, 3350, 2820, 2740, 1685, 1590, 1500, 1390, 1270, 1215, 1160, 1060, 1020, 770cm-1.
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[N:8]([C:12]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:9]=[CH:10][N:11]=1.[O:31]1CCC[CH2:32]1.C(OCC)=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CCCCCC>[C:12]([N:8]1[CH:9]=[CH:10][N:11]=[C:7]1[CH2:6][CH:32]=[O:31])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Cc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C1CCOC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]CCCC
Solvent: CCOC=O
Solvent: CCCCCC
Product: O=CCc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.75 h

Procedure:
1.6 M of n-Butyllithium in hexane (7.5 mL) was added dropwise to a solution of 2-Methyl-1-trityl-1H-imidazole (3.244 g, 10.00 mmol) in Tetrahydrofuran (100.0 mL, 1233 mmol) at −76° C. The dark red mixture was stirred for 45 min. Ethyl formate (4.039 mL, 50.00 mmol) was added quickly and the mixture (turned yellowish) was stirred for 20 min. 6 ml of 5% aq. citric acid were added and the mixture was mixed with 60 ml of aq citric acid and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over MgSO4 and concentrated in vacuum. Pale yellow semisolid material (2.025 g, 57.5%) was used in the next step without further purification.
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[OH:14][C:15]1[C:16]([O:23][CH3:24])=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=[O:19].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH:18]([C:17]1[C:16]([O:23][CH3:24])=[C:15]([CH:22]=[CH:21][CH:20]=1)[O:14][C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5])=[O:19]
Reactant: N#Cc1ccc(C(F)(F)F)cc1F
Reactant: COc1c(O)cccc1C=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1c(C=O)cccc1Oc1cc(C(F)(F)F)ccc1C#N
Yield: 91.1 %

Procedure:
2-Fluoro-4-trifluoromethyl-benzonitrile (0.56 mL, 0.76 g, 4 mmol), 3-hydroxy-2-methoxybenzaldehyde (0.61 g, 4 mmol) and cesium carbonate (1.3 g, 4 mmol) were heated with stirring in dry DMF (4 mL) at 50° C. for 18 h. The reaction mixture was cooled, poured into water and extracted with ethyl acetate. The ethyl acetate layer was separated, washed with water (2×), 10% sodium carbonate solution (2×), water (1×), brine (1×), and dried over MgSO4. After filtration, the solvent was removed in vacuo to yield 2-(3-formyl-2-methoxy-phenoxy)-4-trifluoromethyl-benzonitrile (1.17 g, 91%) as a brown solid.