Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.C([Li])CCC.CON(C)[C:17]([CH:19]1[CH2:24][CH2:23][N:22]([C:25]2[N:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[CH2:21][CH2:20]1)=[O:18].C(Cl)Cl>C1COCC1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:17]([CH:19]2[CH2:20][CH2:21][N:22]([C:25]3[N:26]=[CH:27][CH:28]=[CH:29][N:30]=3)[CH2:23][CH2:24]2)=[O:18])=[CH:3][CH:4]=1
Reactant: CON(C)C(=O)C1CCN(c2ncccn2)CC1
Reactant: Brc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(c1ccc(Br)cc1)C1CCN(c2ncccn2)CC1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 83.1 %

Procedure:
A solution of 1,4-dibromobenzene (2.29 g, 9.72 mmol, 1.9 eq) in THF (20 ml) under N2 was cooled to −78° C., and n-butyllithium (1.6 M in hexanes, 4.8 ml, 7.67 mmol, 1.5 eq) was added dropwise. The reaction mixture was stirred at −78° C. for 40 minutes, and a solution of N-methoxy-N-methyl-1-(pyrimidin-2-yl)piperadine-4-carboxamide (1.28 g, 5.11 mmol, 1 eq) in THF (5 ml) was added dropwise via a cannula. After 3 hours at −78° C., the reaction mixture was warmed to 0° C., stirred for 1 hour, and then quenched with 1 N aq. HCl (10 ml). The mixture was diluted with 150 ml of ethyl acetate, washed sequentially with saturated aq. NaHCO3 and brine (75 ml each), and the organic phase was dried over Na2SO4 and concentrated. Column chromatography (silica gel, CH2Cl2 3.5% ethyl acetate/CH2Cl2) afforded 1.47 g (83% yield) of the product as a pale yellow solid: HPLC: 99% pure at 3.748 min (YMC-Pack ODS-A 4.6×33 mm column, 0% 100% solvent B over 4 min, 3 ml/min, 220 nm); LCMS (M+H)+=345.90; 400 MHz 1H NMR (CDCl3) 8.31 (d, J=4.7 Hz, 2H), 7.83 (d, J=8.5 Hz, 2H), 7.63 (d, J=8.5 Hz, 2H), 6.48 (t, J=4.7 Hz, 1H), 4.81 (m, 2H), 3.49 (m, 1H), 3.08 (m, 2H), 1.72-1.95 (m, 4H).
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:31][CH2:30][C@@:29]2([CH3:32])[C@@H:11]([CH2:12][CH2:13][C:14]3[C:15]4[C@:25]([CH3:33])([CH2:26][CH2:27][C:28]=32)[C@@H:18]([C@H:19]([CH3:24])[CH2:20][CH2:21][CH2:22][OH:23])[CH2:17][CH:16]=4)[C:10]1([CH3:35])[CH3:34])(C(C)(C)C)(C)C.[H-].[Na+].[CH3:38]I>CN(C=O)C>[CH3:35][C:10]1([CH3:34])[C@@H:9]([OH:8])[CH2:31][CH2:30][C@@:29]2([CH3:32])[C@H:11]1[CH2:12][CH2:13][C:14]1[C:15]3[C@:25]([CH3:33])([CH2:26][CH2:27][C:28]=12)[C@@H:18]([C@H:19]([CH3:24])[CH2:20][CH2:21][CH2:22][O:23][CH3:38])[CH2:17][CH:16]=3
Reactant: CI
Reactant: C[C@H](CCCO)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O[Si](C)(C)C(C)(C)C)C(C)(C)[C@@H]1CC3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCC[C@@H](C)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)[C@@H]1CC3

Procedure:
3β-tert-Butyldimethylsilyloxy-4,4-dimethyl-5α-chola-8,14-dien-24-ol (100 mg) is methylated with sodium hydride 60% (16 mg) and methyl iodine (0.125 ml) in 1 ml of DMF. The protecting tert-butyldimethylsilyl group is split of by treatment with HCl/ethanol. After aqueous work-up and crystallisation from methanol/water, the title compound (5 mg) is isolated.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15](O)=[O:16])[CH2:9][CH2:8][C:6]=2[N:7]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[F:33][C:34]1[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][C:35]=1[C:41]([F:44])([F:43])[F:42].O>CS(C)=O.[Cl-].[Na+].O>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([NH:38][C:37]3[CH:39]=[CH:40][C:34]([F:33])=[C:35]([C:41]([F:44])([F:42])[F:43])[CH:36]=3)=[O:16])[CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: Nc1ccc(F)c(C(F)(F)F)c1
Reactant: Nc1ncc2c(n1)CCN(c1cccc(C(=O)O)c1)C2
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Nc1ncc2c(n1)CCN(c1cccc(C(=O)Nc3ccc(F)c(C(F)(F)F)c3)c1)C2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 9.3 %

Procedure:
A mixture of 3-(2-amino-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)benzoic acid (54 mg, 0.20 mmol) and 1,1′-Carbonyldiimidazole (36 mg, 0.22 mmol) in 3.0 mL DMSO was stirred at rt for 5 minutes, and then heated at 60° C. for 25 minutes. Then 4-fluoro-3-(trifluoromethyl)aniline (0.051 mL, 0.40 mmol) was added, and the reaction heated at 80° C. for 46 hours. Next, an additional 2 small drops of 4-fluoro-3-(trifluoromethyl)aniline was added and the reaction heated at 160° C. for 1.5 hours. Upon cooling to rt, the reaction mixture was added to a solution of 35 mL H2O plus 5 mL brine, and the resulting precipitate filtered and rinsed with H2O and hexane/EtOAc. The precipitate was chromatographed using CHCl3/MeOH, and the resulting solid chromatographed again using EtOAc/MeOH to give the title compound as a yellow solid (8 mg, 9%). 1H NMR (Acetone-d6) δ: 9.77 (br. s., 1H), 8.31 (dd, J=6.4, 2.6 Hz, 1H), 8.10-8.17 (m, 2H), 7.62-7.64 (m, 1H), 7.35-7.44 (m, 3H), 7.24-7.28 (m, 1H), 5.79 (br. s., 2H), 4.35 (s, 2H), 3.70 (t, J=5.9 Hz, 2H), 2.80-2.86 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][N:12]([C:14]([N:16]3[CH2:21][CH2:20][N:19]([S:22]([CH3:25])(=[O:24])=[O:23])[CH2:18][CH2:17]3)=[O:15])[CH2:11][CH:10]2[C:26](=O)[CH3:27])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[NH2:30][OH:31].C([O-])(=O)C.[Na+].O>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][N:12]([C:14]([N:16]3[CH2:21][CH2:20][N:19]([S:22]([CH3:25])(=[O:24])=[O:23])[CH2:18][CH2:17]3)=[O:15])[CH2:11][CH:10]2[C:26](=[N:30][OH:31])[CH3:27])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(=O)C1CN(C(=O)N2CCN(S(C)(=O)=O)CC2)CC1c1ccc(Cl)c(Cl)c1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(=NO)C1CN(C(=O)N2CCN(S(C)(=O)=O)CC2)CC1c1ccc(Cl)c(Cl)c1
Yield: 79.8 %

Procedure:
1-[(3SR,4RS)-4-(3,4-Dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-carbonyl)-pyrrolidin-3-yl]-ethanone (0.87 g, 2 mmol), hydroxylamine hydrochloride (0.28 g, 2.05 mmol) and sodium acetate (0.33 g, 2.06 mmol) were dissolved in ethanol (9.0 mL) and heated to reflux for 2 h. After cooling to ambient temperature water (20 mL) was added. The mixture was extracted with ethyl acetate (3×10 mL) and the combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was subjected to column chromatography (silica gel, ethyl acetate) to yield the title compound as a colorless foam (0.74 g, 82%). ES-MS m/e: 437.5 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:16]2[O:17][C:18]3[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=3[N:20]=2)[CH:6]=[CH:7][C:8]=1[CH2:9]C1C=NC=CC=1.BrCC1C=CC(C2OC3[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=3[N:37]=2)=CC=1OC.N1C=CC(B(O)O)=CC=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:16]2[O:17][C:18]3[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=3[N:20]=2)[CH:6]=[CH:7][C:8]=1[CH2:9][C:39]1[CH:38]=[CH:36][N:37]=[CH:41][CH:40]=1
Reactant: COc1cc(-c2nc3ccccc3o2)ccc1Cc1cccnc1
Reactant: COc1cc(-c2nc3ccccc3o2)ccc1CBr
Agent: OB(O)c1ccncc1
Product: COc1cc(-c2nc3ccccc3o2)ccc1Cc1ccncc1

Procedure:
Utilizing the general procedure outlined for 2-[3-methoxy-4-(pyridin-3-ylmethyl)phenyl]-1,3-benzoxazole, 2-[4-(bromomethyl)-3-methoxyphenyl]-1,3-benzoxazole (270 mg, 0.81 mmol), 4-pyridylboronic acid (100 mg, 0.81 mmol) reacted to afford the desired 2-[3-methoxy-4-(pyridin-4-ylmethyl)phenyl]-1,3-benzoxazole as a colorless solid: 1H NMR (CDCl3, 300 MHz) δ 8.46 (br s, 2H), 7.75–7.81 (m, 3H), 7.56–7.59 (m, 1H), 7.34–7.36 (m, 2H), 7.22 (d, 1H), 7.13 (d, 2H), 4.00 (s, 2H), 3.92 (s, 3H). MS (ESI) 317 (M+H)+.
Reaction SMILES: O[CH2:2][CH:3]1[CH2:5][CH:4]1[C:6]1[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=1[C:8]#[N:9].C([N:16](CC)CC)C.CS(Cl)(=O)=O.[OH-].[NH4+]>C(Cl)Cl.C(#N)C>[NH2:16][CH2:2][CH:3]1[CH2:5][CH:4]1[C:6]1[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=1[C:8]#[N:9]
Reactant: CCN(CC)CC
Reactant: N#Cc1ccccc1C1CC1CO
Agent: CS(=O)(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CC#N
Solvent: ClCCl
Product: N#Cc1ccccc1C1CC1CN
Temperature: 25 °C
Yield: 13 %

Procedure:
A cold solution of 2-(2-(hydroxymethyl)cyclopropyl)benzonitrile (425 mg, 2.454 mmol) in methylene chloride (15 mL), and triethyl amine (1.368 mL, 9.81 mmol) was treated with methanesulfonyl chloride (0.287 mL, 3.68 mmol) dropwise with ice bath cooling. The cooling bath was removed, the reaction warmed to rt for 1 hr. The reaction was diluted with methylene chloride washed with water and brine, dried over magnesium sulfate, and concentrated to give a wax. A solution of the material in acetonitrile (15 mL) and ammonium hydroxide (2 mL, 51.4 mmol) was stirred for 16 h at rt. The reaction was concentrated to about ½ volume and diluted with ether. The suspension was extracted with 1N HCl. The acid extracts were made basic with 50% sodium hydroxide, then extracted with methylene chloride (4×). The organics were dried potassium carbonate and concentrated. The resulting dark wax (400 mg) was then purified on silica gel using 1-20% MeOH/methylene chloride to give an orange wax. The wax was triturated with acetone to give 2-(2-(aminomethyl)cyclopropyl)benzonitrile as a white solid (55 mg, 13%). 1H NMR (400 MHz, DMSO-d6) δ 7.91 (br. s., 2H), 7.80 (dd, J=7.8, 1.0 Hz, 1H), 7.65 (td, J=7.8, 1.3 Hz, 1H), 7.40 (td, J=7.6, 1.1 Hz, 1H), 7.20 (d, J=7.8 Hz, 1H), 2.97 (t, J=6.9 Hz, 2H), 2.32-2.19 (m, 1H), 1.68-1.48 (m, 1H), 1.23 (dt, J=8.8, 5.2 Hz, 1H), 1.10 (dt, J=8.7, 5.2 Hz, 1H). LCMS: M+1=173.05.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[N:26]=[C:25]([CH:27]([F:29])[F:28])[CH:24]=[C:23]([C:30]4[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=4)[N:22]=3)[CH:16]=2)[CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:29][CH:27]([F:28])[C:25]1[CH:24]=[C:23]([C:30]2[CH:31]=[CH:32][C:33]([C:36]([F:37])([F:39])[F:38])=[CH:34][CH:35]=2)[N:22]=[C:21]([C:17]2[CH:16]=[C:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([S:6]([NH2:5])(=[O:7])=[O:8])[CH:10]=3)[CH:20]=[CH:19][CH:18]=2)[N:26]=1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)F)n3)c2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1cccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)F)n3)c2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 45.7 %

Procedure:
To a cooled and stirred solution of 3′-[4-difluoromethyl-6-(4-trifluoromethylphenyl)-pyrimidin-2-yl]-biphenyl-3-sulfonic acid tert-butylamide (0.51 g) in dichloromethane (6 ml) was added TFA (6 ml) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness, poured into 2N Na2CO3 solution (20 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. Further purification by flash chromatography on silica gel (ethyl acetate/heptane) and crystallization (ethyl acetate/heptane) yielded the title compound as a white solid (0.21 g, 42%). MS (ISP) 506.1 [(M+H)+]; mp 204° C.
Reaction SMILES: C([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19]([OH:21])=[O:20])=[CH:14][CH:13]=2)[N:9]=1)(=O)C.[CH:22](C1N=C(NC(=O)C)SC=1)=O.Cl>C(O)(=O)C>[CH3:22][O:21][C:19](=[O:20])[CH2:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][CH2:10][C:8]2[N:9]=[C:5]([NH2:4])[S:6][CH:7]=2)=[CH:17][CH:16]=1
Reactant: CC(=O)Nc1nc(C=O)cs1
Reactant: CC(=O)Nc1nc(CCc2ccc(CC(=O)O)cc2)cs1
Agent: Cl
Solvent: CC(=O)O
Product: COC(=O)Cc1ccc(CCc2csc(N)n2)cc1
Temperature: 107.5 °C
Reaction time: 12 h
Yield: 98 %

Procedure:
To {4-[2-(2-acetylamino-1,3-thiazol-4-yl)ethyl]phenyl}acetic acid (6.00 g, 19.7 mmol) that was synthesized from N-(4-formyl-1,3-thiazol-2-yl)acetamide by Wittig reaction and hydrogenation reaction based on the method described in WO2006/28269 were added acetic acid (18 ml) and concentrated hydrochloric acid (24 ml), and the mixture was heated at 105-110° C. for 5 hrs. After cooling, the reaction mixture was concentrated to dryness. 5% Hydrogen chloride methanol solution (30 ml) was added to the residue, and the mixture was stirred at 40° C. for 1.5 hrs and at room temperature for 12 hrs. The reaction mixture was concentrated, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Diisopropyl ether was added to the residue, and the precipitate was collected by filtration, washed with diisopropyl ether and dried under reduced pressure to give methyl{4-[2-(2-amino-1,3-thiazol-4-yl)ethyl]phenyl}acetate (5.36 g, yield 98%) as a white solid.
Reaction SMILES: C(O)C.[Na].[C:5](=[N:8][OH:9])([NH2:7])[CH3:6].[Br:10][C:11]1[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=1[C:13](OC)=O>O>[Br:10][C:11]1[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=1[C:13]1[O:9][N:8]=[C:5]([CH3:6])[N:7]=1
Reactant: CC(N)=NO
Reactant: COC(=O)c1ccccc1Br
Agent: [Na]
Solvent: CCO
Solvent: O
Product: Cc1noc(-c2ccccc2Br)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 33.5 %

Procedure:
To activated molecular sieves (2.0 g, 4 Å powdered) was added ethanol (20 ml) followed by sodium metal (0.435 g, 18.9 mmol), and the mixture heated at reflux for 15 min. After cooling to ambient temperature, acetamide oxime (1.4 g, 18.9 mmol) was added and the suspension stirred for 15 min. Methyl 2-bromobenzoate (1.32 ml, 9.5 mmol) was added and the mixture heated at reflux for 2 h. The reaction was poured into water and extracted with ethyl acetate. The organic phase was separated, dried over magnesium sulfate, filtered and evaporated to give a white solid. The crude product was purified by crystallisation from ethyl acetatelisohexane to give 5-(2-bromophenyl)-3-methyl-[1,2,4]oxadiazole as a white solid (0.76 g): δH (400 MHz, CDCl3) 2.52 (3H, s), 7.45 (2H, m), 7.76 (1H, dd, J 7.8 and 1.2), 7.97 (1H, dd, J 7.8 and 1.2); m/z (ES+) 239:241 (1:1) (M++H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[C:16]4=[C:17]([C@@H:19]5[CH2:24][NH:23][CH2:22][CH2:21][C@@H:20]5[N:15]4[CH2:14][CH2:13][CH2:12]3)[CH:18]=2)=[C:5]([C:25]([F:28])([F:27])[F:26])[CH:4]=1.Br[CH2:30][CH2:31][CH3:32].N>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[C:16]4=[C:17]([C@@H:19]5[CH2:24][N:23]([CH2:30][CH2:31][CH3:32])[CH2:22][CH2:21][C@@H:20]5[N:15]4[CH2:14][CH2:13][CH2:12]3)[CH:18]=2)=[C:5]([C:25]([F:28])([F:26])[F:27])[CH:4]=1
Reactant: COc1ccc(-c2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCC3)c(C(F)(F)F)c1
Reactant: CCCBr
Agent: N
Product: CCCN1CC[C@H]2[C@@H](C1)c1cc(-c3ccc(OC)cc3C(F)(F)F)cc3c1N2CCC3

Procedure:
The title compound was prepared by the method of Example 382 as a yellow oil (23 mg, 69%) from (7aS,11aR)-2-[4-methoxy-2-(trifluoromethyl)phenyl]-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3′,4′:4,5]pyrrolo[3,2,1-ij]quinoline (30 mg, 0.077 mmol) and 1-bromopropane (20 mg, 0.15 mmol). 1H NMR (CDCl3, 300 MHz) δ 0.98 (t, J=7.3 Hz, 3H), 1.78-1.92 (br, 2H), 2.11-2.25 (m, 5H), 2.28-2.42 (m, 1H), 2.53-2.80 (m, 5H), 3.05-3.25 (br, 2H), 3.31 (dt, J=10.2, 3.6 Hz, 1H), 3.37-3.45 (br, 1H), 3.60-3.72 (br, 1H), 3.89 (s, 3H), 6.85 (s, 1H), 6.87 (s, 1H), 7.05 (dd, J=8.7, 2.6 Hz, 1H), 7.21-7.27 (m, 2H) ppm. MS (CI, NH3): 431.2 (base, M+H).
Reaction SMILES: ClC1C=CC=C(F)C=1C=O.ClC1C=CC=C(F)C=1C=C.[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:23]=1[C@H:29]1[CH2:31][C@H:30]1[N:32]=[C:33]=[O:34].[NH2:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]#[N:43])=[CH:38][N:37]=1>>[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:23]=1[C@H:29]1[CH2:31][C@H:30]1[NH:32][C:33]([NH:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]#[N:43])=[CH:38][N:37]=1)=[O:34]
Reactant: O=C=N[C@@H]1C[C@@H]1c1c(F)cccc1Cl
Reactant: N#Cc1ccc(N)nc1
Agent: C=Cc1c(F)cccc1Cl
Agent: O=Cc1c(F)cccc1Cl
Product: N#Cc1ccc(NC(=O)N[C@@H]2C[C@@H]2c2c(F)cccc2Cl)nc1

Procedure:
2-chloro-6-fluorobenzaldehyde (Aldrich), was converted to 2-chloro-6-fluorostyrene according to the method described in Example 377 of WO 93/03022 and then to cis-2-(2-chloro-6-fluorophenyl) cyclopropylisocyanate analogously to the method described in Example 348 of WO 93/03022. This compound was then condensed with 2-amino-5-cyanopyridine of Example 41 in a manner analogous to the method in Example 7 to provide N-(cis-2-(2-chloro-6-fluorophenyl)-cyclopropyl)-N'-(5-cyanopyrid-2-yl)-urea: Mp 189° C. 1H-NMR (250 MHz, DMSO-d6): 1.2 (m, 1H), 1.45-1.55 (m, 1H), 2.2-2.3 (m, 1H), 3.3-3.4 (m, 1H), 7.35-7.6 (m, 4H), 7.9-8.1 (m, 2H), 9.5 (s, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:26])[CH:3]=[N:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([C:14](=O)[CH:15]([CH3:24])[C:16]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[S:17])=[CH:10][CH:9]=1)(=[O:7])=[O:6].C(=O)([O-])[O-].[K+].[K+].I[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36]>CC(C)=O>[CH2:38]([O:37][C:35]([C:34]1[S:17][C:16]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[C:15]([CH3:24])[C:14]=1[C:11]1[CH:12]=[CH:13][C:8]([S:5](=[O:7])(=[O:6])[N:4]=[CH:3][N:2]([CH3:26])[CH3:1])=[CH:9][CH:10]=1)=[O:36])[CH3:39]
Reactant: CC(C(=O)c1ccc(S(=O)(=O)N=CN(C)C)cc1)C(=S)N1CCOCC1
Reactant: CCOC(=O)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1sc(N2CCOCC2)c(C)c1-c1ccc(S(=O)(=O)N=CN(C)C)cc1
Temperature: 57.5 °C
Reaction time: 2 h
Yield: 43.4 %

Procedure:
To a stirred solution of N,N-dimethyl-N′-((4-(2-methyl-3-morpholino-3-thioxopropanoyl)phenyl)sulfonyl)formimidamide (compound 24c, 0.180 g, 0.45 mmol) in dry acetone (15 ml) was added potassium carbonate (0.45 g, 3.17 mmol) at room temperature. The resulting mixture was stirred at 55-60° C. for 2 hr. The reaction mixture was cooled to 0° C. and to this was added ethyl iodoacetate (0.097 g, 0.053 ml, 0.45 mmol) in a dropwise manner. The reaction mixture was stirred at reflux temperature for 4 hr. The progress of the reaction was monitored by TLC. The reaction mixture was allowed to warm to room temperature and filtered through a celite pad. The celite pad was washed with acetone (2×10 ml). The filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography over silica gel (100-200 mesh) using 50-55% ethyl acetate in hexanes as an eluent to obtain the title compound (0.091 g, 43%)
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.[Br-].[CH:13]1([Zn+])[CH2:15][CH2:14]1>C1COCC1.O.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>[CH:13]1([C:2]2[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=2)[CH2:15][CH2:14]1
Reactant: [Zn+]C1CC1
Reactant: COC(=O)c1ccc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(C2CC2)cn1
Temperature: 80 °C
Yield: 73.1 %

Procedure:
To a sealed tube were added methyl 5-bromopicolinate (700 mg, 3.24 mmol) in THF (10 ml). The reaction mixture was purged with Ar followed by addition of tetrakis(triphenylphosphine)palladium (187 mg, 0.162 mmol) and finally cyclopropylzinc bromide solution 0.5 m in tetrahydrofuran (7.78 mL, 3.89 mmol). The tube was sealed and heated to 80° C. for 1.5 hrs. Then it was diluted with water, and extracted with EtOAc. The organic layer was washed with brine and concentrated to give crude product. The crude material was purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 25% to 40% to 60% EtOAc in Heptane, to provide methyl 5-cyclopropylpicolinate (420 mg, 2.370 mmol, 73.1% yield) as off-white solid. MS m/z=178.2 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[C:11]#[CH:12].I[C:14]1[CH:23]=[C:18]([C:19]([O:21][CH3:22])=[O:20])[C:17]([OH:24])=[CH:16][CH:15]=1.C1C=CC=CC=1.C(N(CC)CC)C>O=O.[Cu]I>[CH3:22][O:21][C:19](=[O:20])[C:18]1[CH:23]=[C:14]([C:12]#[C:11][C:4]2[CH:5]=[C:6]([O:9][CH3:10])[CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH:15]=[CH:16][C:17]=1[OH:24]
Reactant: C#Cc1cc(OC)ccc1OC
Reactant: COC(=O)c1cc(I)ccc1O
Agent: [Cu]I
Agent: O=O
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: COC(=O)c1cc(C#Cc2cc(OC)ccc2OC)ccc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under argon atmosphere 240 mg of 2,5-dimethoxyphenylacetylene and 493 mg of methyl 5-iodosalicylate are dissolved in 20 ml of oxygen-free and dry benzene. The mixture is treated with 85 mg of tetrakis (triphenylphosphine)palladium, 20 mg of copper(I)iodide and 450 mg of triethylamine, stirred at room temperature overnight and then poured onto 100 ml of aqueous pH 7 buffer. After extraction with ethyl acetate and purification by chromatography on silicagel, 5-[2-(2,5-dimethoxyphenyl)ethinyl]-2-hydroxybenzoic acid methyl ester is obtained (colorless crystals of M.P. 105°-108°).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][C:3]=1[C:10]#[N:11].[N-:12]=[N+:13]=[N-:14].[Na+]>C(O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:12]=[N+:13]=[N-:14])=[CH:4][C:3]=1[C:10]#[N:11]
Reactant: N#Cc1cc(CBr)ccc1Cl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCO
Product: N#Cc1cc(CN=[N+]=[N-])ccc1Cl
Reaction time: 18 h
Yield: 97.8 %

Procedure:
A stirred mixture of 4-chloro-3-cyanobenzyl bromide (3.0 g, 13 mmol) and sodium azide (1.26 g, 19.4 mmol) was refluxed 5 hours in absolute ethanol (30 mL). The mixture was kept 18 hours at ambient temperature, filtered, and the filtrate was evaporated under vacuum. The residue was triturated with diethyl ether, filtered, and evaporated to provide 2.45 g (98%) liquid 4-chloro-3-cyanobenzyl azide; I.R. (neat): 2240, 2100 cm1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH2:8].[C:9](OC(OCC)OCC)(=O)C>C(OCC)(=O)C>[N:8]1[C:7]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=2[NH:1][CH:9]=1
Reactant: Nc1ccncc1N
Reactant: CCOC(OCC)OC(C)=O
Solvent: CCOC(C)=O
Product: c1cc2nc[nH]c2cn1

Procedure:
3H-Imidazolo[4,5-c]pyridine was prepared by the method of Stanovik and Tisler, Synthesis, 2, 120 (1974). A mixture of 2.2 g (0.02 mole) of 3,4-diaminopyridine and 5 ml diethoxymethyl acetate was heated at reflux for two hours. The reaction mixture was cooled and diluted by addition of ethyl acetate. The solid precipitate was collected by filtration and sublimed at 170° C. and 50 torr to give 0.84 g of 3H-imidazolo[4,5-c]pyridine; mp 165°-168° C.
Reaction SMILES: [O:1]1[C@H:5]2[O:6][CH2:7][CH2:8][C@H:4]2[C@@H:3]([O:9][C:10](=[O:32])[NH:11][C@@H:12]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@H:13]([OH:24])[CH2:14][NH:15][CH2:16][C:17]([CH3:23])([CH3:22])[CH2:18][CH2:19][C:20]#[N:21])[CH2:2]1.C(N(C(C)C)CC)(C)C.[C:42]([NH:45][C:46]1[CH:47]=[C:48]([S:53](Cl)(=[O:55])=[O:54])[CH:49]=[CH:50][C:51]=1[F:52])(=[O:44])[CH3:43]>C(Cl)Cl>[O:1]1[C@H:5]2[O:6][CH2:7][CH2:8][C@H:4]2[C@@H:3]([O:9][C:10](=[O:32])[NH:11][C@@H:12]([CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C@H:13]([OH:24])[CH2:14][N:15]([S:53]([C:48]2[CH:49]=[CH:50][C:51]([F:52])=[C:46]([NH:45][C:42](=[O:44])[CH3:43])[CH:47]=2)(=[O:54])=[O:55])[CH2:16][C:17]([CH3:22])([CH3:23])[CH2:18][CH2:19][C:20]#[N:21])[CH2:2]1
Reactant: CC(C)(CCC#N)CNC[C@@H](O)[C@H](Cc1ccccc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21
Reactant: CC(=O)Nc1cc(S(=O)(=O)Cl)ccc1F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1cc(S(=O)(=O)N(C[C@@H](O)[C@H](Cc2ccccc2)NC(=O)O[C@H]2CO[C@H]3OCC[C@H]32)CC(C)(C)CCC#N)ccc1F
Yield: 39.3 %

Procedure:
[(1S,2R)-1-Benzyl-3-(4-cyano-2,2-dimethylbutylamino)-2-hydroxy-propyl]-carbamic acid (3R,3aS,6aR)hexahydro-furo[2,3-b]furan-3-yl ester (0.020 g, 0.05 mmol) was dissolved in CH2Cl2 and treated with diisopropylethylamine (0.025 ml, 0.13 mmol) and 3-acetamido-4-fluorobenzenesulfonyl chloride (0.012 g, 0.05 mmol) at ambient temperature under argon with stirring. After 15 h the reaction mixture was concentrated in vacuo, taken up in EtOAc, washed with sat. aq. NaHCO3, and brine. The organic phase was dried over MgSO4, filtered and solvent removed in vacuo. Purification by preparative thin layer chromatography (3% MeOH in CH2Cl2) gave 0.013 g of a white solid. MS (ES): 661 (M+1).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4]([NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:3]=1.O.[NH2:22][NH2:23]>>[NH:22]([C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4]([NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:3]=1)[NH2:23]
Reactant: Cn1cnc2c(NCCc3ccccc3)nc(Cl)nc21
Reactant: NN
Solvent: O
Product: Cn1cnc2c(NCCc3ccccc3)nc(NN)nc21

Procedure:
Was prepared according to Example 8 from (2-chloro-9-methyl-9H-purin-6-yl)phenethyl-amine and hydrazine monohydrate.