Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[CH3:12][N:13]([CH3:25])[C:14]([C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1)=[O:15]>>[CH3:12][N:13]([CH3:25])[C:14](=[O:15])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:2]2[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=2)[CH:17]=1
Reactant: CN(C)C(=O)c1cccc(B(O)O)c1
Reactant: Cc1cc([N+](=O)[O-])cnc1Br
Product: Cc1cc([N+](=O)[O-])cnc1-c1cccc(C(=O)N(C)C)c1
Yield: 94 %

Procedure:
Obtained (0.620 g, yield 94%) following the procedure described in Intermediate 27, starting with 2-bromo-3-methyl-5-nitropyridine (2.30 mmol, 0.500 g), 3-(dimethyl-carbamoyl)phenylboronic acid (2.33 mmol, 0.450 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][C:5]([Cl:8])=[CH:4][N:3]=1.[NH:9]1[CH:13]=[N:12][CH:11]=[N:10]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Cl:8][C:5]1[CH:4]=[N:3][C:2]([N:9]2[CH:13]=[N:12][CH:11]=[N:10]2)=[CH:7][N:6]=1
Reactant: Clc1cnc(Cl)cn1
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1cnc(-n2cncn2)cn1

Procedure:
2,5-Dichloropyrazine (298 mg, 2.0 mmol) and 1,2,4-triazole (145 mg, 2.1 mmol) were added in DMF (10 mL), then cesium carbonate was added and the reaction was at room temperature over night. Water (20mL) was added, extracted with ethyl acetate (30 mL), second wash with brine (20 mL). The organic phase was dried by magnesium sulfate, filtered, concentrated and purified by column chromatography through a 25 gram Biotage SNAP KP-Sil™ silica gel cartridge eluting with 22% ethyl acetate/hexanes to give the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][N:7]2[C:16](=[O:17])[C:15]([C:18]3[NH:23][C:22]4[CH:24]=[CH:25][C:26](I)=[CH:27][C:21]=4[S:20](=[O:30])(=[O:29])[N:19]=3)=[C:14]([OH:31])[C@H:13]3[C@@H:8]2[C@H:9]2[CH2:32][C@@H:12]3[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[Cu][C:36]#[N:37].CN(C)C=O>C(OCC)(=O)C>[F:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][N:7]2[C:16](=[O:17])[C:15]([C:18]3[NH:23][C:22]4[CH:24]=[CH:25][C:26]([C:36]#[N:37])=[CH:27][C:21]=4[S:20](=[O:30])(=[O:29])[N:19]=3)=[C:14]([OH:31])[C@H:13]3[C@@H:8]2[C@H:9]2[CH2:32][C@@H:12]3[CH2:11][CH2:10]2)=[CH:4][CH:3]=1
Reactant: N#C[Cu]
Reactant: O=C1C(C2=NS(=O)(=O)c3cc(I)ccc3N2)=C(O)[C@@H]2[C@H]3CC[C@H](C3)[C@@H]2N1Cc1ccc(F)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)[C@@H]3[C@H]4CC[C@H](C4)[C@@H]3N(Cc3ccc(F)cc3)C1=O)N2
Temperature: 120 °C
Reaction time: 24 h
Yield: 96.2 %

Procedure:
(1R,2S,7R,8S)-3-(4-Fluoro-benzyl)-6-hydroxy-5-(7-iodo-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-3-aza-tricyclo[6.2.1.02,7]undec-5-en-4-one (0.5 g, 0.84 mmol) and copper(I) cyanide (0.151 g, 1.7 mmol) were suspended anhydrous N,N-dimethylformamide (4 mL). The mixture was stirred at 120° C., under nitrogen for 24 h. Upon cooling, the mixture was diluted with ethyl acetate (20 mL) and washed with saturated aqueous ammonium chloride solution (3×15 mL). The organic phase was passed through a short plug of Celite followed by a short plug of silica gel (Merck silica gel 60, 40-63 μm), eluting with ethyl acetate. The filtrate was concentrated in vacuo to afford a yellow solid. Purification by flash column chromatography (Teledyne Isco RediSep column; 25-100% ethyl acetate in hexanes) followed by concentration in vacuo afforded the desired product, (1R,2S,7R,8S)-3-[3-(4-fluoro-benzyl)-6-hydroxy-4-oxo-3-aza-tricyclo[6.2.1.02,7]undec-5-en-5-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazine-7-carbonitrile (0.398 g, 0.808 mmol, 96%), as a white, brittle foam. 1H NMR (400 MHz, DMSO-d6) δ: 1.15-1.15 (1H, m), 1.34-1.61 (5H, m), 2.48-2.48 (1H, m), 2.60 (1H, d, J=3.3 Hz), 2.90 (1H, d, J=9.4 Hz), 3.48 (1H, d, J=9.4 Hz), 4.38 (1H, d, J=15.6 Hz), 4.96 (1H, d, J=15.4 Hz), 7.11-7.16 (2H, m), 7.31 (2H, dd, J1=8.6 Hz, J2=5.4 Hz), 7.60 (1H, d, J=8.6 Hz), 8.02 (1H, dd, J1=8.6 Hz, J2=2.5 Hz), 8.37 (1H, s). LC-MS (ESI) calculated for C25H21FN4O4S 492.13. found 493.1 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:40])=[C:4]([C@@H: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])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:35]=[CH:34][N:33]([CH2:36][C:37]([OH:39])=O)[N:32]=2)=[O:29])[CH:5]=[CH:6][CH:7]=1.N.C[N:43](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>[C:37]([CH2:36][N:33]1[CH:34]=[CH:35][C:31]([NH:30][C:28]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:40])[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]([CH3:25])([CH3:27])[CH3:26])[NH:10]2)=[O:29])=[N:32]1)(=[O:39])[NH2:43]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccn(CC(=O)O)n2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)Nc2ccn(CC(N)=O)n2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of rac-(3-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-pyrazol-1-yl)-acetic acid (85 mg, 0.144 mmol), ammonia (0.57 mL, 0.288 mmol, 0.5 M in dioxane), 2-(7-azabenzotriazol-1-yl)-n,n,n′,n′-tetramethyluronium hexafluorophosphate (HATU, 109 mg, 0.288 mmol) and iPr2NEt (0.1 mL, 0.43 mmol) in CH2Cl2 (10 mL) was stirred at rt overnight. The mixture was then diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, dried over Na2SO4 and filtered. The mixture was then concentrated and purified by reverse phase chromatography (20-95% of ACN/water) rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide (12.3 mg, 14.5%) as an off-white powder. HRMS (ES+) m/z Calcd for C28H28Cl2F2N6O2+H [(M+H)+]: 589.1692. found: 589.1693.
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:12]([CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][NH:15]1)#[N:13]>>[C:12]([CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][N:15]1[CH2:10][CH2:9][CH2:8][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)#[N:13]
Reactant: BrCCCOc1ccccc1
Reactant: N#CC1CCCCN1
Product: N#CC1CCCCN1CCCOc1ccccc1

Procedure:
Following the procedure of Preparation 9, the title compound is prepared from 3-phenoxypropyl bromide and 2-cyanopiperidine [Chem. Ber. 92, 1608-1613 (1959), Helv. Chim. Acta 46(4), 1190-1206 (1963)].
Reaction SMILES: [CH3:1][CH:2]([OH:5])[CH2:3][CH3:4].CN1CCOCC1.[C:13](Cl)(=[O:21])[O:14][CH2:15][O:16][C:17](=[O:20])[CH2:18][CH3:19]>C(Cl)(Cl)Cl>[C:13](=[O:21])([O:14][CH2:15][O:16][C:17](=[O:20])[CH2:18][CH3:19])[O:5][CH:2]([CH2:3][CH3:4])[CH3:1]
Reactant: CCC(=O)OCOC(=O)Cl
Reactant: CCC(C)O
Solvent: CN1CCOCC1
Solvent: ClC(Cl)Cl
Product: CCC(=O)OCOC(=O)OC(C)CC
Temperature: 25 °C
Reaction time: 1 h
Yield: 49 %

Procedure:
To a solution of 2-butanol (0.92 mL, 10 mmol) and 4-methylmorpholine (1.1 mL, 10 mmol) in CHCl3 (20 mL) at -70° C. is added 7c (1.7 g, 10 mmol) during 20 min with stirring. The temperature is kept at -70° C. for 1 h and then raised (1 h) to room temperature. Next day following evaporation the residue is triturated with Et2O (25 mL) and filtered. The filtrate is evaporated and distilled to give 1.0 g (50%) of the title compound with bp 66°-68° C./5 mbar.
Reaction SMILES: Br[C:2]1[C:6]2[N:7]=[CH:8][N:9]=[C:10]([O:11][CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[C:5]=2[S:4][CH:3]=1.[CH3:25][S:26]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)(=[O:28])=[O:27].C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[CH3:25][S:26]([C:29]1[CH:34]=[CH:33][C:32]([C:2]2[C:6]3[N:7]=[CH:8][N:9]=[C:10]([O:11][CH:12]4[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]4)[C:5]=3[S:4][CH:3]=2)=[CH:31][CH:30]=1)(=[O:28])=[O:27]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ncnc3c(Br)csc23)CC1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ncnc3c(-c4ccc(S(C)(=O)=O)cc4)csc23)CC1
Temperature: 100 °C
Reaction time: 12 h
Yield: 21.2 %

Procedure:
Tert-butyl 4-(7-bromothieno[3,2-d]pyrimidin-4-yloxy)piperidine-1-carboxylate (100 mg), 4-methanesulfonyl-phenylboronic acid (72 mg), Pd(PPh3)4 (17 mg) and 2N Na2CO3 (0.72 mL) were added to 1,4-dioxane (2 mL), and stirred at 100° C. for 12 hours in a hermetically sealed reactor. The reaction mixture was cooled to room temperature, extracted with ethyl acetate and distilled water, and the organic layer thus obtained was washed with water and a saline solution. Subsequently, the washed organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (25 mg).
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.[OH-].[K+].[Cl:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18]([CH3:23])=[CH:17]2.ClCCN1CCOCC1>CS(C)=O>[Cl:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[N:19]([CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)[C:18]([CH3:23])=[CH:17]2
Reactant: ClCCN1CCOCC1
Reactant: Cc1cc2cc(Cl)ccc2[nH]1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Cc1cc2cc(Cl)ccc2n1CCN1CCOCC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-chloroethylmorpholine HCl (100 mg, 0.60 mmol) in 0.3 mL DMSO was added pulverized KOH (102 mg, 1.81 mmol), then after 10 min, a solution of 5-chloro-2-methylindole (134 mg, 0.72 mmol) in 0.2 mL DMSO was added and the reaction stirred at room temperature overnight. Additional 2-chloroethylmorpholine (22 mg, 0.12 mmol) and KOH (17 mg, 0.3 mmol) added and stirred overnight. The reaction mixture was partitioned between H2O and toluene, and the organic extract washed two times with H2O, dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified via silica gel chromatography using a gradient from 0 to 5% MeOH in CH2Cl2 to give a final yield of 154 mg (0.55 mmol). 1H NMR (500 MHz, CDCl3, δ): 2.47 (s, 3H), 2.48-2.57 (m, 4H), 2.63 (t, J=7.2 Hz, 2H), 3.73 (t, J=4.4 Hz, 4H), 4.16 (t, J=7.2 Hz, 2H), 6.20 (s, 1H), 7.11 (dd, J=8.6 Hz, 1.7 Hz, 1H), 7.19 (d, J=8.6 Hz, 1H), 7.50 (d, J=1.5 Hz, 1H). 13C NMR (500 MHz, CDCl3, δ): 12.88, 41.23, 54.13, 57.86, 66.95, 99.88, 109.78, 119.15, 120.64, 124.97, 129.18, 134.99, 138.03. MS m/z 279.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]([C:12]([F:15])([F:14])[F:13])=[CH:3][C@H:4]1[C@H:6]([C:7](O)=[O:8])[C:5]1([CH3:11])[CH3:10].N1C=CC=CC=1.S(Cl)([Cl:24])=O>C1(C)C=CC=CC=1>[Cl:1][C:2]([C:12]([F:15])([F:14])[F:13])=[CH:3][C@H:4]1[C@H:6]([C:7]([Cl:24])=[O:8])[C:5]1([CH3:11])[CH3:10]
Reactant: O=S(Cl)Cl
Reactant: CC1(C)[C@@H](C=C(Cl)C(F)(F)F)[C@@H]1C(=O)O
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC1(C)[C@@H](C=C(Cl)C(F)(F)F)[C@@H]1C(=O)Cl
Temperature: 25 °C
Reaction time: 17 h
Yield: 84.1 %

Procedure:
To a stirred solution of 4.1 g (0.0173 mole) of (+)-trans-3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarboxylic acid in 40 ml of toluene at ambient temperature was added 1.7 g (0.022 mole) of pyridine, then 2.6 g (0.022 mole) of thionyl chloride in 25 ml of toluene. Upon complete addition the reaction mixture was stirred at ambient temperature for 17 hours. The reaction mixture was filtered through diatomaceous earth, and the filtrate was evaporated under reduced pressure to give 3.8 g of (+)-trans-3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarbonyl chloride. The ir spectrum was consistent with the assigned structure.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:21]([NH:24][C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1)(=[O:23])[CH3:22]>S1(CCCC1)(=O)=O.[Cu]>[C:21]([NH:24][CH:25]1[CH2:30][CH2:29][NH:28][CH:27]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[N:3]=2)[CH2:26]1)(=[O:23])[CH3:22]
Reactant: Clc1cccc(Oc2ccccc2)n1
Reactant: CC(=O)Nc1ccncc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Product: CC(=O)NC1CCNC(c2cccc(Oc3ccccc3)n2)C1
Temperature: 150 °C
Reaction time: 40 h
Yield: 30 %

Procedure:
A mixture of 0.116 moles of 2-chloro-6-phenoxypyridine, 21.5 g of anhydrous potassium carbonate, 0.151 moles of 4-acetamidopyridine and 0.118 mole of copper in powder form in 100 ml of sulfolane is heated to 150° C. with stirring for 40 hours. The sulfolane is distilled, the residue is taken up with water, the suspension is treated with water and it is extracted with methylene chloride. The organic phase is washed with water, dried and concentrated to dryness. By crystallisation of the residue in diisopropylic ether, 4-acetamido-2-(6-phenoxy-2-pyridyl)piperidine is obtained; m.p. 104° to 106° C.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6]([CH2:9][O:10][C:11]3[CH:19]=[CH:18][CH:17]=[C:16]4[C:12]=3[CH:13]=[C:14]([C:20]([OH:22])=O)[NH:15]4)=[CH:7][O:8][C:4]=2[CH:3]=1.[ClH:25].Cl.Cl.[NH2:28][CH:29]1[CH2:34][CH2:33][N:32]([CH2:35][CH2:36][N:37]2[CH2:42][CH2:41][CH:40]([OH:43])[CH2:39][CH2:38]2)[CH2:31][CH2:30]1>>[ClH:25].[ClH:25].[OH:43][CH:40]1[CH2:39][CH2:38][N:37]([CH2:36][CH2:35][N:32]2[CH2:31][CH2:30][CH:29]([NH:28][C:20]([C:14]3[NH:15][C:16]4[C:12]([CH:13]=3)=[C:11]([O:10][CH2:9][C:6]3[C:5]5[CH:23]=[CH:24][C:2]([F:1])=[CH:3][C:4]=5[O:8][CH:7]=3)[CH:19]=[CH:18][CH:17]=4)=[O:22])[CH2:34][CH2:33]2)[CH2:42][CH2:41]1
Reactant: NC1CCN(CCN2CCC(O)CC2)CC1
Reactant: O=C(O)c1cc2c(OCc3coc4cc(F)ccc34)cccc2[nH]1
Agent: Cl
Product: O=C(NC1CCN(CCN2CCC(O)CC2)CC1)c1cc2c(OCc3coc4cc(F)ccc34)cccc2[nH]1

Procedure:
This compound is synthesized from 4-(6-fluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (106, see example 55) and amine 21 analogously to the method described in example 1.
Reaction SMILES: O[C:2]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]=1)([CH3:6])[C:3]([OH:5])=[O:4].O>O1CCOCC1.S(=O)(=O)(O)O>[CH2:13]([C:9]1[CH:8]=[C:7]([C:2](=[CH2:6])[C:3]([OH:5])=[O:4])[CH:12]=[CH:11][CH:10]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(O)(C(=O)O)c1cccc(Cc2ccccc2)c1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C1COCCO1
Product: C=C(C(=O)O)c1cccc(Cc2ccccc2)c1

Procedure:
136 g (0.531 mol) of 2-hydroxy-2-(3-benzyl-phenyl)-propanoic acid (product from Example 11) are refluxed in a mixture of 3 l of dioxane and 180 ml of concentrated sulphuric acid. Water is added to the mixture which has been concentrated to approximately 500 ml and the mixture is extracted three times with ether. After drying the organic phases using saturated NaCl and magnesium sulphate, a brown oil remains, which is purified by filtration on 1 kg of silica gel (ethyl acetate/cyclohexane 5:1). Yield: 83 g (66%).
Reaction SMILES: [C:1]([C:4]1[S:5][CH:6]=[C:7]([C:9]([OH:11])=O)[N:8]=1)(=[O:3])[CH3:2].[NH2:12][C@H:13]([CH3:29])[CH2:14][N:15]1[CH:19]=[CH:18][C:17]([C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[C:22]([Cl:28])[CH:21]=2)=[N:16]1>>[C:1]([C:4]1[S:5][CH:6]=[C:7]([C:9]([NH:12][C@H:13]([CH3:29])[CH2:14][N:15]2[CH:19]=[CH:18][C:17]([C:20]3[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[C:22]([Cl:28])[CH:21]=3)=[N:16]2)=[O:11])[N:8]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1nc(C(=O)O)cs1
Reactant: C[C@@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Product: CC(=O)c1nc(C(=O)N[C@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)cs1
Yield: 24.22 %

Procedure:
(R)-2-acetyl-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)thiazole-4-carboxamide was prepared using the method of Example 34(d) starting from 2-acetylthiazole-4-carboxylic acid (0.597 g, 3.07 mmol) and (R)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.8 g, 3.07 mmol). The product was triturated using diethyl ether, isopropanol and DCM, respectively. Yield 24.22%. 1H-NMR (400 MHz; DMSO-d6): δ 1.19 (d, 3H), 2.30 (s, 3H), 4.37 (dd, 1H), 4.44 (dd, 1H), 4.47-4.56 (m, 1H), 6.96 (d, 1H), 7.87 (d, 1H), 7.92 (dd, 1H), 7.97 (d, 1H), 7.04 (d, 1H), 8.49 (d, 1H), 8.61 (s, 1H).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[OH:18][C:19]1[C:23]([OH:24])=[C:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[N:21]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)[C:20]=1[C:38]([O:40][CH2:41][CH3:42])=[O:39]>CCO>[CH2:1]([O:18][C:19]1[C:23]([OH:24])=[C:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[N:21]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)[C:20]=1[C:38]([O:40][CH2:41][CH3:42])=[O:39])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1c(O)c(O)c(C(=O)OCC)n1-c1ccc(OC)cc1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1c(O)c(OCc2ccccc2)c(C(=O)OCC)n1-c1ccc(OC)cc1
Temperature: 50 °C
Reaction time: 18 h
Yield: 46 %

Procedure:
Benzyl bromide (2.13 ml, 17.9 mmol) was added dropwise to a suspension of DIPEA (3.12 mL, 17.9 mmol) and diethyl 3,4-dihydroxy-1-(4-methoxyphenyl)-1H-pyrrole-2,5-dicarboxylate (UL2-001) (5 g, 14.3 mmol) in EtOH (200 mL). The reaction mixture was stirred at 50° C. for 18 h. Additional benzyl bromide (0.85 mL, 7.20 mmol) and DIPEA (1.25 mL, 7.20 mmol) were added and the reaction stirred at 60° C. for 24 h, after which further portions of benzyl bromide (0.85 ml, 7.20 mmol) and DIPEA (1.25 mL, 7.20 mmol) were added and the reaction mixture stirred at 60° C. for 24 h. The reaction mixture was allowed to cool to RT, and partitioned between EtOAc (200 mL) and sat. NaHCO3 (aq.) (200 mL), the organic layer was separated and washed with sat. NaHCO3 (aq.) (2×200 mL) dried (MgSO4), filtered and solvents removed in vacuo to give an orange oil. The residue was purified by silica gel chromatography (80 g, 0-100% EtOAc in isohexane) to afford a yellow solid. The product was recrystallised from EtOH (100 mL) to afford diethyl 3-(benzyloxy)-4-hydroxy-1-(4-methoxyphenyl)-1H-pyrrole-2,5-dicarboxylate (23) (2.89 g, 37%) as a pale yellow solid: m/z 440 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 8.82 (s, 1H), 7.52-7.30 (m, 5H), 7.16-7.03 (m, 2H), 6.94-6.83 (m, 2H), 5.09 (s, 2H), 4.10-3.91 (m, 4H), 3.79 (s, 3H), 1.02-0.92 (m, 6H).
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[C:19]#[N:20]>>[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[N:24]1[CH2:29][CH2:28][N:27]([C:4](=[O:6])[C:3]2[CH:7]=[C:8]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:9]=[CH:10][C:2]=2[I:1])[CH2:26][CH2:25]1)[C:19]#[N:20]
Reactant: N#Cc1ccc(N2CCNCC2)c(F)c1
Reactant: CS(=O)(=O)c1ccc(I)c(C(=O)O)c1
Product: CS(=O)(=O)c1ccc(I)c(C(=O)N2CCN(c3ccc(C#N)cc3F)CC2)c1

Procedure:
Example CL was prepared in analogy to Example 123 from 2-Iodo-5-methanesulfonyl-benzoic acid (example BQ) and 3-Fluoro-4-piperazin-1-yl-benzonitrile (WO9625414). MS (m/e): 514.0 (M+H+, 100%).
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10]1[N:20]=[CH:19][CH:18]=[CH:17][C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[CH:29]([C:35]([O-])=[O:36])[C:30]([O:32][CH2:33][CH3:34])=[O:31]>ClCCl>[CH2:1]([O:8][N:9]([C:35](=[O:36])[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:10]1[N:20]=[CH:19][CH:18]=[CH:17][C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(Cl)C(=O)[O-]
Reactant: CCOC(=O)c1cccnc1NOCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(=O)N(OCc1ccccc1)c1ncccc1C(=O)OCC
Reaction time: 2 h
Yield: 64.7 %

Procedure:
A solution of the product of Example 157A (1.2 g, 4.4 mmol) and triethylamine (0.49 g, 4.8 mmol) in dichloromethane (25 mL) was treated dropwise with ethyl chloromalonate (0.73 g, 4.8 mmol), stirred for 2 hr and partitioned between ethyl acetate and water and the layers were separated. The ethyl acetate layer was washed with brine, dried (Na2SO4), and concentrated. The residue was purified by column chromatography on silica gel eluting with hexane and ethyl acetate (3:1) to provide the title compound (1.1 g, 65%). MS (DCI) m/z 387 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:9][NH:10][CH2:11][CH2:12][C:13]2[N:14]=[CH:15][N:16]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH:17]=2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[F:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]([C:38]2[C:39]([CH:44]=O)=[N:40][CH:41]=[CH:42][CH:43]=2)([CH3:37])[CH3:36])=[CH:31][CH:30]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:1][C:2]1[C:3]([CH2:9][N:10]([CH2:44][C:39]2[C:38]([C:35]([C:32]3[CH:31]=[CH:30][C:29]([F:28])=[CH:34][CH:33]=3)([CH3:37])[CH3:36])=[CH:43][CH:42]=[CH:41][N:40]=2)[CH2:11][CH2:12][C:13]2[N:14]=[CH:15][N:16]([S:18]([C:21]3[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=3)(=[O:19])=[O:20])[CH:17]=2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cnc(CCNCc3ncc(C)cc3C)c2)cc1
Reactant: CC(C)(c1ccc(F)cc1)c1cccnc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2cnc(CCN(Cc3ncc(C)cc3C)Cc3ncccc3C(C)(C)c3ccc(F)cc3)c2)cc1
Yield: 39 %

Procedure:
Using General Procedure B: Reaction of (3,5-dimethyl-pyridin-2-ylmethyl)-{2-[1-(toluene-4-sulfonyl)-1H-imidazol-4-yl]-ethyl}-amine and 3-[1-(4-fluoro-phenyl)-1-methyl-ethyl]pyridine-2-carbaldehyde in CH2Cl2 with NaBH(OAc)3 gave (3,5-dimethyl-pyridin-2-ylmethyl)-{3-[1-(4-fluoro-phenyl)-1-methyl-ethyl]-pyridin-2-ylmethyl}-{2-[1-{toluene-4-sulfonyl)-1H-imidazol-4-yl]-ethyl}-amine (87.3 mg, 39%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[N:3]=1.C(NC(C)C)(C)C.[Li].[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[CH:29]=[O:30]>C1COCC1>[Cl:1][C:2]1[C:7]([CH:29]([C:25]2[S:24][CH:28]=[CH:27][CH:26]=2)[OH:30])=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[N:3]=1
Reactant: O=Cc1cccs1
Reactant: Clc1ccnc(Oc2ccccc2Cl)n1
Agent: [Li]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: OC(c1cccs1)c1cnc(Oc2ccccc2Cl)nc1Cl
Temperature: -78 °C
Reaction time: 0.13 h

Procedure:
4-Chloro-2-(2-chloro-phenoxy)-pyrimidine (432 mg, 1.79 mmol) was dissolved in 10 mL of dry THF, and the reaction mixture was cooled to −78° C. under nitrogen. Lithium diisopropylamine (1.6 mL of 2M solution in THF) was added and the reaction mixture was stirred for eight minutes. Thiophene-2-carboxaldehyde (0.31 mL) was added, and the reaction mixture was stirred for 30 minutes at −78° C. The reaction was quenched by addition of 10 mL saturated aqueous ammonium chloride, and evaporated under reduced pressure to remove THF. Water (40 mL) and EtOAc (60 mL) were added, the organic phase was collected, and the aqueous phase was washed twice with 40 mL EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered, and evaporated under reduced pressure. The residue was purified by preparative TLC using 1.8% MeOH in methylene chloride to yield 98 mg of [4-Chloro-2-(2-chloro-phenoxy)-pyrimidin-5-yl]-thiophen-2-yl-methanol. Mass Spec. M+H=354.
Reaction SMILES: [NH2:1][C:2]([O:4][CH2:5][CH3:6])=[O:3].[Br:7][C:8]1[CH:21]=[CH:20][C:19]2[O:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]([C:22](Cl)=[O:23])[C:10]=2[CH:9]=1>>[CH2:5]([O:4][C:2](=[O:3])[NH:1][C:22]([CH:11]1[C:10]2[CH:9]=[C:8]([Br:7])[CH:21]=[CH:20][C:19]=2[O:18][C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:23])[CH3:6]
Reactant: CCOC(N)=O
Reactant: O=C(Cl)C1c2ccccc2Oc2ccc(Br)cc21
Product: CCOC(=O)NC(=O)C1c2ccccc2Oc2ccc(Br)cc21

Procedure:
The title compound, light brown solid, m.p. 203° C. and MS: m/e=375 (M+) was prepared in accordance with the general method of example 6 from urethane and 2-bromo-9H-xanthene-9-carbonyl chloride.