Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[N:13]1[CH:14]=[CH:15][N:16]2[CH2:21][CH:20]([CH2:22][OH:23])[CH2:19][CH2:18][C:17]=12.O.Cl.Cl.[CH2:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:29][CH:28]1[NH:36][C:37]1[N:38]=[CH:39][C:40]2[CH2:45][NH:44][CH2:43][C:41]=2[N:42]=1.C(N(C(C)C)CC)(C)C>ClCCl>[CH2:29]1[C:30]2[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:27][CH:28]1[NH:36][C:37]1[N:38]=[CH:39][C:40]2[CH2:45][N:44]([C:1]([O:23][CH2:22][CH:20]3[CH2:21][N:16]4[CH:15]=[CH:14][N:13]=[C:17]4[CH2:18][CH2:19]3)=[O:2])[CH2:43][C:41]=2[N:42]=1
Reactant: c1ccc2c(c1)CC(Nc1ncc3c(n1)CNC3)C2
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: OCC1CCc2nccn2C1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: O=C(OCC1CCc2nccn2C1)N1Cc2cnc(NC3Cc4ccccc4C3)nc2C1
Temperature: 40 °C
Reaction time: 1 h
Yield: 44.4 %

Procedure:
Add 1,1′-carbonyldiimidazole (2.87 g; 1.02 equiv; 17.69 mmoles) to a solution of 5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-6-ylmethanol (2.64 g; 1.00 equiv; 17.35 mmoles) in dichloromethane (30 mL), then stir at 40° C. for 1 hour. Add N-(2,3-dihydro-1H-inden-2-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-amine dihydrochloride hydrate (6.25 g; 1.05 equiv; 18.21 mmoles) and diisopropylethylamine (9.08 mL; 3.0 equiv; 52.04 mmoles) and maintain the reaction at 40° C. for 4 hours. Load the solution directly onto a diisopropylethylamine treated silica gel column and purify the mixture by column chromatography (0 to 15% methanol in ethyl acetate) to give 5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-6-ylmethyl 2-(2,3-dihydro-1H-inden-2-ylamino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (3.32 g; 44%) as a colorless foam. MS (m/z): 431(M+1).
Reaction SMILES: FC1C=C(C)C=CC=1[N+]([O-])=O.[CH:12]([O:15][C:16]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:17]=1[NH2:18])([CH3:14])[CH3:13].[NH2:24][C:25]1[S:26][CH:27]=[CH:28][N:29]=1.C[CH:31]([OH:33])C>>[CH:12]([O:15][C:16]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:17]=1[NH:18][C:31]([NH:24][C:25]1[S:26][CH:27]=[CH:28][N:29]=1)=[O:33])([CH3:14])[CH3:13]
Reactant: Nc1nccs1
Reactant: Cc1ccc(N)c(OC(C)C)c1
Reactant: CC(C)O
Agent: Cc1ccc([N+](=O)[O-])c(F)c1
Product: Cc1ccc(NC(=O)Nc2nccs2)c(OC(C)C)c1
Yield: 62 %

Procedure:
3-(2-Isopropoxy)-4-nitrotoluene (0.72 g, 74%) was prepared from 2-propanol and 3-fluoro-4-nitrotoluene (0.77 g, 5.0 mmol) following the general procedure G. This was reduced to 2-isopropoxy-4-methyl-aniline (0.42 g, 70%) following general procedure C. 1-(2-Isopropoxy-4-methyl-phenyl)-3-thiazol-2-yl-urea (180 mg, 62%) was prepared from 2-isopropoxy-4-methyl-aniline (165 mg, 1.0 mmol) and 2-aminothiazole (100 mg, 1.0 mmol) following the general procedure D.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([CH2:26][OH:27])=[CH:22][CH:21]=2)[C:11]2[S:12][CH:13]=[C:14]([CH:16]([CH3:18])[CH3:17])[N:15]=2)=[CH:4][CH:3]=1.[F:28][C:29]1[CH:34]=[C:33](O)[CH:32]=[CH:31][C:30]=1[CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1>[F:28][C:29]1[CH:34]=[C:33]([O:27][CH2:26][C:23]2[CH:22]=[CH:21][C:20]([CH2:19][N:10]([CH2:9][CH2:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[C:11]3[S:12][CH:13]=[C:14]([CH:16]([CH3:18])[CH3:17])[N:15]=3)=[CH:25][CH:24]=2)[CH:32]=[CH:31][C:30]=1[CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39]
Reactant: CCOC(=O)CCc1ccc(O)cc1F
Reactant: CC(C)c1csc(N(CCc2ccc(F)cc2)Cc2ccc(CO)cc2)n1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)CCc1ccc(OCc2ccc(CN(CCc3ccc(F)cc3)c3nc(C(C)C)cs3)cc2)cc1F
Yield: 64.2 %

Procedure:
A solution of (4-{[[2-(4-fluorophenyl)ethyl](4-isopropyl-1,3-thiazol-2-yl)amino]methyl}phenyl)methanol (510 mg), ethyl 3-(2-fluoro-4-hydroxyphenyl)propanoate (280 mg), triphenylphosphine (420 mg) and diethyl azodicarboxylate (40% toluene solution, 750 mg) in toluene (3 mL) was stirred at room temperature for 1 hr. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:19-1:1 in volume ratio) to give the title compound (490 mg, yield 64%) as a yellow oil.
Reaction SMILES: C([O:8][C:9](=[O:47])[CH2:10][N:11]([C:16](=[O:46])[C@H:17]([CH2:39][CH2:40][CH2:41][NH:42][C:43](=[NH:45])[NH2:44])[N:18]([N+:36]([O-])=O)[S:19]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[CH:23]=1)(=[O:21])=[O:20])[CH2:12][CH2:13][CH2:14][CH3:15])C1C=CC=CC=1.C(O)(=O)C.O.[H][H]>C(O)C.[Pd]>[N:18]#[N:36].[CH:30]1([C:24]2[CH:23]=[C:22]([S:19]([NH:18][C@H:17]([C:16]([N:11]([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:10][C:9]([OH:47])=[O:8])=[O:46])[CH2:39][CH2:40][CH2:41][NH:42][C:43](=[NH:44])[NH2:45])(=[O:21])=[O:20])[CH:27]=[CH:26][C:25]=2[O:28][CH3:29])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: [H][H]
Reactant: CCCCN(CC(=O)OCc1ccccc1)C(=O)[C@H](CCCNC(=N)N)N([N+](=O)[O-])S(=O)(=O)c1ccc(OC)c(C2CCCCC2)c1
Agent: [Pd]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: CCCCN(CC(=O)O)C(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c1ccc(OC)c(C2CCCCC2)c1
Product: N#N
Yield: 72 %

Procedure:
To a solution of 3.00 g of NG -nitro-N2 -(3-cyclohexyl-4-methoxyphenylsulfonyl)-L-arginyl-N-butylglycine benzyl ester in 50 ml of ethanol, 10 ml of acetic acid and 10 ml of water was added 0.5 g of palladium-black and then the mixture was shaken in a hydrogen atmosphere for 50 hours at room temperature. At the end of this period, the ethanol solution was filtered to remove the catalyst and evaporated to dryness. The residue was washed several times with dry ethyl ether and chromatographed on 80 ml of Daiaion® SK 102 ion exchange resin (200-300 mesh, H+ form, manufactured by Mitsubishi Chemical Industries Limited) packed in water, washed with water, and eluted with 3% ammonium hydroxide solution. The fraction eluted from 3% ammonium hydroxide solution was evaporated to dryness to give 1.5 g (72%) of N2 -(3-cyclohexyl-4-methoxyphenylsulfonyl)-L-arginyl-N-butylglycine as an amorphous solid. I.R. (KBr): 3,350, 2,920, 1,630, 1,250 cm-1
Reaction SMILES: [O:1]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][N:6]=1)[CH:2]([CH3:4])[CH3:3]>C(O)(=O)C.CCOC(C)=O.[Fe]>[O:1]([C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][N:6]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Oc1ccc([N+](=O)[O-])cn1
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)Oc1ccc(N)cn1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 99.1 %

Procedure:
A 100 mL round-bottom flask was charged with the iron powder (5.6 g, 10 mmol) in acetic acid (30 mL) and heated to 80° C. (oil bath) under N2. To this mixture was added slowly the above 2-isopropoxyl-5-nitropyridine (4.6 g, 25.2 mmol) in acetic acid (30 mL) via dropping funnel and the reaction stirred at 80° C. for another 30 min after the addition. After cooling the reaction mixture, it was diluted with EtOAc, filtered through celite, and the solvent evaporated in vacuo. The residue was dissolved in EtOAc and washed with NaHCO3 (sat.), brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified through automated normal-phase chromatography to afford 2-isopropoxyl-5-aminopyridine (3.8 g, 99%) which was used directly for the next step: 1H NMR (400 MHz, CDCl3) δ 7.64 (d, 1H), 7.00 (dt, 1H), 6.52 (d, 1H), 5.10 (sep, 1H), 1.30 (d, 6H); MS (ES) (M++H) expect 153.1. found 153.1.
Reaction SMILES: Cl.[CH2:2]([N:9]([CH2:30]C(OCC1C=CC=CC=1)=O)[C:10](=[O:29])[C@H:11]([NH:21][C:22]([O:24]C(C)(C)C)=O)[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[C:3]1C=C[CH:6]=[CH:5][CH:4]=1.O1CCO[CH2:43][CH2:42]1>ClCCl>[CH2:2]([N:9]1[CH2:30][C:22](=[O:24])[NH:21][C@H:11]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)[C:10]1=[O:29])[C:3]1[CH:43]=[CH:42][CH:6]=[CH:5][CH:4]=1
Reactant: C1COCCO1
Reactant: COc1ccc(C[C@@H](NC(=O)OC(C)(C)C)C(=O)N(CC(=O)OCc2ccccc2)Cc2ccccc2)cc1
Agent: Cl
Solvent: ClCCl
Product: COc1ccc(C[C@H]2NC(=O)CN(Cc3ccccc3)C2=O)cc1
Reaction time: 2 h

Procedure:
4N Hydrogen chloride in 1,4-dioxane solution (48 ml) was added dropwise to a solution of N-benzyl-N-benzyloxycarbonylmethyl-(2R)-2-(tert-butoxycarbonylamino)-3-(4-methoxyphenyl)propionamide (8.48 g) in dichloromethane (48 ml) under ice-bath cooling. After being stirred for 2 hours at the same temperature, the reaction mixture was concentrated under reduced pressure. The residue was added to aqueous sodium bicarbonate solution (50 ml) and dichloromethane (50 ml), and the organic layer was separated, washed with brine, dried over sodium sulfate, and evaporated under reduced pressure to give a powder of (3R)-1-benzyl-3-(4-methoxybenzyl)piperazine-2,5-dione (3.65 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[O:8])[CH:2]=1.[OH-].[K+].[N+:11]([CH2:13][C:14]([N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)=[O:15])#[C-:12]>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C@@H:7]2[O:8][CH:12]=[N:11][C@H:13]2[C:14]([N:16]2[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)=[O:15])[CH:2]=1
Reactant: [C-]#[N+]CC(=O)N1CCOCC1
Reactant: O=Cc1cccnc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C([C@@H]1N=CO[C@H]1c1cccnc1)N1CCOCC1
Temperature: 0 °C
Reaction time: 20 h
Yield: 72.5 %

Procedure:
SLA 09050A was prepared in accordance with method D using pyridine-3-carbaldehyde (0.65 mL, 4.86 mmol), KOH (0.273 mg, 4.86 mmol) in methanol (10 mL) and 2-isocyano-1-morpholinoethanone SLA 07118 (0.75 g, 4.86 mmol). The solution was stirred for 20 h at 0° C. After work-up (without any further purification), evaporation and drying trans-(4,5-dihydro-5-(pyridin-3-yl)oxazol-4-yl)(morpholino)methanone SLA 09050A was obtained as a yellow solid (0.92 g, 72.5% yield).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[CH:9][C:10]2[CH2:16][CH2:15][C:14]3[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=3[C:12](=[CH:21][CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[C:11]=2[CH:27]=1.[O:28]1[CH2:32]CCC1.CS(C)=[O:35]>>[CH3:26][N:24]([CH3:25])[CH2:23][CH2:22]/[CH:21]=[C:12]1/[C:13]2[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=2[CH2:15][CH2:16][C:10]2[CH:9]=[CH:8][C:7]([C:32]([OH:28])=[O:35])=[CH:27][C:11]/1=2
Reactant: CS(C)=O
Reactant: C1CCOC1
Reactant: CN(C)CCC=C1c2ccccc2CCc2ccc(Br)cc21
Agent: [Li]CCCC
Product: CN(C)CC/C=C1/c2ccccc2CCc2ccc(C(=O)O)cc21
Temperature: -70 °C
Reaction time: 0.17 h

Procedure:
A solution of n-butyl lithium (6 mmole) was added dropwise to an E/Z (1:1) isomeric mixture of 3-(3-bromo-10,11-dihydrodibenzo[a,d]cyclohepten-5-ylidene)-N,N-dimethylpropylamine (1.98 g., 5.6 mmole) in 100 ml. dry tetrahydrofuran at -70° C. under a nitrogen atmosphere. After the yellowish orange solution was stirred at -70° C. for an additional 10 minutes, gaseous carbon dioxide was bubbled through the reaction medium for 30 min. to give a pale yellow solution. The reaction mixture was allowed to warm gradually to room temperature, and was then concentrated under reduced pressure. The residue was dissolved in water, and then the solution was neutralized with 1N hydrochloric acid. The crude E/Z (1:1) mixture was chromatographed on a reverse phase PRP-1 semi-preparative column with 15% acetonitrile in water to give 0.05 g. of the E-isomer and 0.08 g. of the Z-isomer. Both isomers were obtained as lyophilized powders, without definitive melting points. Rechromatography of the resulting isomeric mixture (0.8 g.) yielded more pure E-isomer (0.09 g.), Z-isomer (0.16 g.) and also an E/Z (1:1) isomeric mixture (0.10 g). pmr (E-isomer) (DMSO/d6) δ: 7.79 (d, J=1.6 Hz, 1H, H4), 7.68 (dd, J=7.9, 1.6 Hz, 1H, H2), 7.12-7.29 (m, 5H, aromatic), 5.88 (t, J=7.2 Hz, 1H, CH=), 3.30 (m, 2H, CH2Ar), 2.85 (m, 2H, CH2Ar), 2.35-2.45 (m, 4H, NCH2CH 2), 2.10 (s, 6H, NMe2). pmr (Z-isomer) (DMSO/d6) δ: 7.78 (dd, J=7.8, 1.7 Hz, 1H, H2), 7.66 (d, J=1.5 Hz, 1H, H4), 7.36 (d, J=7.8 Hz, 1H, H1), 7.04-7.26 (m, 4H, aromatic), 5.86 (t, J=7.2 Hz, 1H, CH=), 3.32 (m, 2H, CH2Ar), 2.85, (m, 2H, CH2Ar), 2.10-2.44 (m, 4H, NCH2CH2), 2.07 (s, 6H, NMe2).
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][N:10]([C:12]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=3[C:14]#[N:15])[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH:21]([C:24]1[N:29]=[CH:28][C:27]([CH2:30][NH2:31])=[CH:26][N:25]=1)([CH3:23])[CH3:22].C(N(CC)C(C)C)(C)C>C(#N)C>[CH:21]([C:24]1[N:29]=[CH:28][C:27]([CH2:30][NH:31][C:2]2[C:3]3[CH2:11][N:10]([C:12]4[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=4[C:14]#[N:15])[CH2:9][CH2:8][C:4]=3[N:5]=[CH:6][N:7]=2)=[CH:26][N:25]=1)([CH3:23])[CH3:22]
Reactant: CC(C)c1ncc(CN)cn1
Reactant: Cc1ccc(N2CCc3ncnc(Cl)c3C2)c(C#N)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(N2CCc3ncnc(NCc4cnc(C(C)C)nc4)c3C2)c(C#N)c1

Procedure:
A reaction mixture of 2-(4-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-5-methylbenzonitrile (80 mg, 0.28 mmol) and (2-isopropylpyrimidin-5-yl)methanamine (60 mg, 0.40 mmol) (prepared similarly according to the method for Intermediate 13) in acetonitrile (1 mL) and N,N-diisopropylethylamine (0.3 mL, 2 mmol) was subjected to microwave irradiation at 185° C. for 3 h. The reaction mixture was concentrated and purified by semi-preparative HPLC (100×20.2 mm, C18 column; 40-60% CH3CN-water [10 mM Et2NH]) to yield a light yellow solid.
Reaction SMILES: [C:1]([C:5]([NH:7][C@@H:8]([C@@H:12]([C:14]1[O:18][N:17]=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][C:20]=2[Cl:29])[N:15]=1)[CH3:13])[C:9](O)=[O:10])=[O:6])([CH3:4])([CH3:3])[CH3:2].[NH:30]1[CH2:37][CH2:36][CH2:35][C@H:31]1[C:32]([NH2:34])=[O:33].C1C=NC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[C:1]([C:5]([NH:7][C@@H:8]([C@@H:12]([C:14]1[O:18][N:17]=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][C:20]=2[Cl:29])[N:15]=1)[CH3:13])[C:9]([N:30]1[CH2:37][CH2:36][CH2:35][C@H:31]1[C:32]([NH2:34])=[O:33])=[O:10])=[O:6])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@H](c1nc(-c2ccc(S(C)(=O)=O)cc2Cl)no1)[C@H](NC(=O)C(C)(C)C)C(=O)O
Reactant: NC(=O)[C@@H]1CCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@H](c1nc(-c2ccc(S(C)(=O)=O)cc2Cl)no1)[C@H](NC(=O)C(C)(C)C)C(=O)N1CCC[C@H]1C(N)=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To the crude acid from Step D (0.15 g, 0.33 mmol) in 5 mL of dichloromethane was added L-prolineamide (0.057 g, 0.49 mmol), HOAt (0.090 g, 0.66 mmol), N,N-diisopropylethylamine (0.17 mL, 0.99 mmol) and HATU (0.25 g, 0.66 mmol). After stirring at room temperature for 12 h, the reaction was diluted with dichloromethane. The organic phase was washed sequentially with two portions of 0.5N aqueous sodium bicarbonate solution and saturated aqueous brine, dried over sodium sulfate, and evaporated in vacuo. Purification by HPLC (YMC Pro-C18 column, gradient elution, 10-90% acetonitrile/water with 0.1% TFA) afforded the title compound. LC/MS 556.2 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15]C(=O)CC(NC3C=CC(F)=CC=3)=O)=[CH:11][C:10]=2[F:29])[CH:5]=[CH:4][N:3]=1.CC(C)([O-])C.[K+].ClC1C=CN=C([C:43]([NH2:45])=[O:44])C=1>CN(C=O)C>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:43]([NH2:45])=[O:44])[CH:7]=2)=[C:10]([F:29])[CH:11]=1
Reactant: NC(=O)c1cc(Cl)ccn1
Reactant: O=C(CC(=O)Nc1ccc(Oc2ccnc(Cl)c2)c(F)c1)Nc1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)c1cc(Oc2ccc(N)cc2F)ccn1
Temperature: 110 °C
Reaction time: 1 h
Yield: 82.2 %

Procedure:
A solution of 4-amino-2-fluorophenol (Compound A of Example 20, 0.81 g, 6.4 mmol, 1.0 eq) in DMF (6.5 mL) was treated with potassium tert-butoxide (0.79 g, 7.1 mmol, 1.1 eq) at room temperature and the reaction mixture was stirred for 1 h. 4-Chloropicolinamide (1.0 g, 6.4 mmol, 1.0 eq) was added and the reaction mixture was heated to 110° C. for 8 h. The reaction was cooled to room temperature and the reaction mixture quenched with water. The resulting heterogeneous solution was filtered and the solid material was washed with water. The solid was triturated with a small amount of MeOH followed by Et2O. The solid was filtered and dried in vacuo to afford the product (1.3 g, 82%) as a solid. 1H NMR (DMSO-d6) δ 8.49-8.50 (m, 1H), 8.12 (br s, 1H), 7.71 (br s, 1H), 7.35-7.36 (m, 1H), 7.14-7.16 (m, 1H), 7.01-7.06 (m, 1H), 6.44-6.47 (m, 2H), 5.53 (s, 2H); MS (ESI+) m/z 248 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:28])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][NH:9]2)[CH:5]=[CH:6][CH:7]=1.[CH2:29]([O:31][C:32](=[O:46])[C:33]1[CH:38]=[CH:37][C:36]([CH2:39][C:40](O)=[O:41])=[CH:35][C:34]=1[O:43][CH2:44][CH3:45])[CH3:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:29]([O:31][C:32](=[O:46])[C:33]1[CH:38]=[CH:37][C:36]([CH2:39][C:40]([N:9]2[CH2:10][C@@H:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[C@@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:8]2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[F:28])=[O:41])=[CH:35][C:34]=1[O:43][CH2:44][CH3:45])[CH3:30]
Reactant: CC(C)(C)CC1CNC(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: CCOC(=O)c1ccc(CC(=O)O)cc1OCC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1ccc(CC(=O)N2C[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)cc1OCC
Yield: 80 %

Procedure:
In a manner similar to the method described in Example 4, rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (42.3 mg, 0.10 mmol) was reacted with 4-carboxymethyl-2-ethoxy-benzoic acid ethyl ester (Aldrich, 50.4 mg, 0.20 mmol), in the presence of HATU (91.0 mg, 0.24 mmol) and iPr2NEt (0.1 mL) in CH2Cl2 (2 mL) at rt for 2 hrs to give rac-4-{2-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidin-1-yl]-2-oxo-ethyl}-2-ethoxy-benzoic acid ethyl ester (52.6 mg, 37.6%) which was used in the next step without further purification.
Reaction SMILES: [OH-].[Na+].Br[CH2:4][C:5]([OH:7])=[O:6].[CH3:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([CH3:18])[C:16]=1[OH:17])[CH:12]=[O:13].Cl>O>[CH:12]([C:11]1[CH:14]=[C:15]([CH3:18])[C:16]([O:17][CH2:4][C:5]([OH:7])=[O:6])=[C:9]([CH3:8])[CH:10]=1)=[O:13]
Reactant: Cc1cc(C=O)cc(C)c1O
Reactant: O=C(O)CBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(C=O)cc(C)c1OCC(=O)O
Temperature: 100 °C
Reaction time: 24 h
Yield: 15.2 %

Procedure:
A solution of sodium hydroxide (2.53 g, 63.25 mmol) in water (65 mL) was added to a mixture of bromoacetic acid (5.27 g, 37.95 mmol) and 3,5-dimethyl-4-hydroxy-benzaldehyde (1.9 g, 12.65 mmol) in water (30 mL). The reaction mixture was stirred at 100° C. for 24 h. The solution was acidified to pH ˜2 with conc. HCl. The brown solid was filtered off, washed with water, dried under vacuum, and purified by column chromatography to give (4-formyl-2,6-dimethyl-phenoxy)-acetic acid as a light brown solid (0.40 g). To a solution of 2-amino-4,6-dimethoxybenzamide (0.150 g, 0.764 mmol) in N,N-dimethyl acetamide (5 mL) were added (4-formyl-2,6-dimethyl-phenoxy)-acetic acid (0.159 g, 0.764 mmol), sodium hydrogen sulphite (58.5%, 0.150 g, 0.84 mmol) and p-toluenesulfonic acid (15 mg, 0.0764 mmol). The reaction mixture was stirred at 150° C. for 3 h. it was then cooled to room temperature and water (40 mL) was added. A yellow precipitate was formed and filtered off, washed with water and a small amount of methanol. Triturated with 10% methanol in ether to give 0.084 g of compound, which was further purified by preparative HPLC to give 2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)acetic acid (47 mg, 13%) as a white solid. Selected data: MS (ES) m/z: 384.0; MP 270-272° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][C:3]=1[N+:11]([O-])=O.C(Cl)Cl.[H][H]>[Pd].CO>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][C:3]=1[NH2:11]
Reactant: O=[N+]([O-])c1cc2cn[nH]c2cc1F
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: Nc1cc2cn[nH]c2cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.5 %

Procedure:
To the product of Step (c) (530 mg, 2.93 mmol, 1 equiv) and 10% Pd/C (200 mg) was added CH2Cl2 (10 mL) and MeOH (40 mL). The atmosphere was replaced with hydrogen gas and the solution was stirred at room temperature and atmospheric pressure for 2 hours. The reaction mixture was filtered through a plug of celite and rinsed with MeOH and CH2Cl2. The residue was purified by flash chromatography (linear gradient, 40→70% EtOAc/hexanes) affording 330 mg (75%) of the title compound as a pale purple solid. MS (ES+) m/e 152 [M+H].
Reaction SMILES: Cl.[S:2]1[C:6]2[S:7][CH2:8][CH:9]([NH2:11])[CH2:10][C:5]=2[CH:4]=[CH:3]1.C(N(C(C)C)C(C)C)C.[C:21](Cl)(=[O:24])[CH2:22][CH3:23]>C(Cl)Cl>[C:21]([NH:11][CH:9]1[CH2:8][S:7][C:6]2[S:2][CH:3]=[CH:4][C:5]=2[CH2:10]1)(=[O:24])[CH2:22][CH3:23]
Reactant: CCC(=O)Cl
Reactant: NC1CSc2sccc2C1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC(=O)NC1CSc2sccc2C1
Reaction time: 0.5 h

Procedure:
A mixture of 8.31 g of 5,6-dihydro-4H-thieno[2,3-b]- thiopyran-5-amine hydrochloride, 17.4 ml of ethyldiisopropylamine, 4.07 g of propionyl chloride in 80 ml of methylene chloride is kept for 30 minutes at room temperature. The reaction mixture is washed with 1N hydrochloric acid and then with saturated sodium bicarbonate solution, the organic layer is dried over magnesium sulfate and the solvent is removed in vacuo to yield N-propionyl-5,6-dihydro-4H-thieno[2,3-b]-thiopyran-5-amine. This is refluxed for 3 hours with 85 ml of 1M borane in tetrahydrofuran. Water and 3N hydrochloric acid are added and the mixture is heated briefly. Basification of the aqueous layer followed by extraction with ether affords an oil after removal of solvent. Addition of ethanolic hydrochloric acid affords N-propyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-5-amine hydrochloride, m.p. 107°-110°.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:3]=1[CH2:4][P:5](=[O:12])([O:9]CC)[O:6]CC.Br[Si](C)(C)C.O>ClCCl.CO>[F:1][C:2]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:3]=1[CH2:4][P:5](=[O:6])([OH:9])[OH:12]
Reactant: CCOP(=O)(Cc1c(F)cccc1F)OCC
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: O=P(O)(O)Cc1c(F)cccc1F
Reaction time: 6 h
Yield: 76.1 %

Procedure:
Diethyl 2,6-difluorobenzylphosphonate (2.00 g, 7.57 mmol) was dissolved in dry dichloromethane (20 mL). Bromotrimethylsilane (3.3 mL, 25 mmol) was added via syringe. The reaction was capped with a greased glass stopper and allowed to stir for 6 hours. The volatiles were removed under reduced pressure to yield a yellow oil. This was dissolved in 10:1 methanol:water (20 mL) and allowed to stir overnight. After removing the solvents, recrystallization in acetonitrile yielded a white crystalline solid (1.199 g, 76% yield). 1H NMR (400.14 MHz, DMSO) δ 7.29 (m), 7.04 (m, 2H), 2.96 (d, J=20.99 Hz, 2H). 31P{1H} NMR (161.97 MHz, DMSO): δ 19.51. Analysis calculated (found) %: C, 40.40 (40.64), H, 3.39 (3.34).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][CH:13]([CH3:16])[CH2:14][OH:15])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[H][H]>>[CH:1]([CH:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11][CH2:12][CH:13]([CH3:16])[CH2:14][OH:15])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(CO)CCCc1ccc(C(C)C)cc1
Reactant: [H][H]
Product: CC(CO)CCCC1CCC(C(C)C)CC1
Reaction time: 15 h
Yield: 97.3 %

Procedure:
100 g of 5-(4-Isopropylphenyl)-2-methyl-1-pentanol (obtained as described in EP 0 908 439) combined with 1.5 g Ru on aluminium oxide (Ru content 5 wt. %) were hydrogenated at a hydrogen pressure of 25 bar and at a temperature of 110° C. After 15 hours the reaction was finished. The catalyst was removed and the product distilled. 100 g (content 99.7%) of 5-(4-isopropylcyclohexyl)-2-methyl-1-pentanol were obtained.