Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH2:7]2.[S:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[C:16]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[N:15]1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>CC(CC(C)C)=O>[S:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[C:16]([N:23]2[CH2:24][CH2:25][N:26]([CH2:2][CH2:3][C:4]3[CH:5]=[C:6]4[C:10](=[CH:11][CH:12]=3)[NH:9][C:8](=[O:13])[CH2:7]4)[CH2:27][CH2:28]2)=[N:15]1
Reactant: O=C1Cc2cc(CCCl)ccc2N1
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: O=C1Cc2cc(CCN3CCN(c4nsc5ccccc45)CC3)ccc2N1

Procedure:
To a 125 ml round-bottomed flask equipped with N2 inlet and condenser were added 0.62 g (3.20 mmol) 5-(2-chloroethyl)-oxindole, 0.70 g (3.20 mmol) N-(1,2-benzisothiazol-3-yl)piperazine, 0.68 g (6.40 mmol) sodium carbonate, 2 mg sodium iodide, and 30 ml methylisobutyl ketone. The reaction was refluxed 40 hours, cooled, filtered, and evaporated. The residue was chromatographed on silica gel, eluting the byproducts with ethyl acetate (1 l) and the product with 4% methanol in ethyl acetate (1.5 l). The product fractions (Rf =0.2 in 5% methanol in ethyl acetate) were evaporated, taken up in methylene chloride, and precipitated by addition of ether saturated with HCl; the solid was filtered and washed with ether, dried, and washed with acetone. The latter was done by slurrying the solid with acetone and filtering. The title compound was obtained as a high melting, non-hygroscopic solid product, m.p. 288°-288.5° C., 0.78 g (59%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11]Cl)[N:10]=2)[CH:7]=1.[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[C:18]([CH:21]=1)[C:19]#[N:20]>>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([N:22]2[CH2:23][CH2:24][N:25]([CH2:11][C:9]3[N:10]=[C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]4[CH:8]=3)[CH2:26][CH2:27]2)=[C:18]([CH:21]=1)[C:19]#[N:20]
Reactant: N#Cc1cc(Cl)ccc1N1CCNCC1
Reactant: ClCc1cn2cc(Cl)ccc2n1
Product: N#Cc1cc(Cl)ccc1N1CCN(Cc2cn3cc(Cl)ccc3n2)CC1
Yield: 62.2 %

Procedure:
Following the general procedure of Example 11 and making non-critical variations, 6-chloro-2-(chloromethyl)imidazo[1,2-α]pyridine (Example 4, Step 1; 0.292 g) and 5-chloro-2-(piperazin-1-yl)benzonitrile (0.385 g) are converted to 0.349 g of the title compound after chromatography on silica gel and crystallization from ethyl ether/dichloromethane/hexane. mp 191-191.5° C.; MS m/z 385, 387; IR (mineral oil) 1486, 1330, 806, 1495, 826 cm-1 ; 1H NMR (CDCl3) δ2.77, 3.24, 3.78, 6.93, 7.12, 7.42, 7.51, 8.14.
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[C:10]([C@@H:12]([NH2:14])[CH3:13])[N:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[C:8]=2[C:21]=1[CH3:22].Cl[C:24]1[N:32]=[CH:31][N:30]=[C:29]2[C:25]=1[N:26]=[CH:27][N:28]2C1CCCCO1.CCN(C(C)C)C(C)C>CC(O)C>[F:3][C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[C:10]([C@@H:12]([NH:14][C:24]3[N:32]=[CH:31][N:30]=[C:29]4[C:25]=3[N:26]=[CH:27][NH:28]4)[CH3:13])[N:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[C:8]=2[C:21]=1[CH3:22]
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: Cc1c(F)ccc2nc([C@H](C)N)n(-c3ccccn3)c12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Cc1c(F)ccc2nc([C@H](C)Nc3ncnc4[nH]cnc34)n(-c3ccccn3)c12
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 51.5 %

Procedure:
To a solution of (S)-1-(6-fluoro-7-methyl-1-pyridin-2-yl-1H-benzoimidazol-2-yl)ethylamine dihydrochloride (300 mg, 0.87 mmol) in IPA (10 mL) was added 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (271 mg, 1.14 mmol) and DIPEA (448 μL, 2.62 mmol) and the reaction mixture heated at 90° C. for 16 h. The reaction mixture was concentrated in vacuo and the resultant residue subjected to flash chromatography (SiO2, eluting with 0-10% methanol in EtOAc). LCMS (Method C): RT=2.81 min, [M+H]+=473. The product was dissolved HCl in methanol (5 mL, 2.5M) and the reaction stirred at RT for 30 min. The reaction mixture was concentrated in vacuo and the resultant residue loaded onto an SCX 2 cartridge, washed with methanol then eluted with ammonia in methanol (2M). The eluent was concentrated in vacuo and the residue triturated with diethyl ether to give 288 as a white solid (174 mg, 51%) 1H NMR 400 MHz δ (DMSO-d6 80° C.): 8.55-8.49 (1H, m), 8.01 (1H, s), 7.89 (1H, td, J=7.7, 1.9 Hz), 7.65 (1H, d, J=7.6 Hz), 7.49 (1H, dd, J=8.7, 4.7 Hz), 7.46 (1H, ddd, J=7.6, 4.9, 0.9 Hz), 7.17 (1H, br s), 7.02 (1H, dd, J=10.6, 9.0 Hz), 5.57 (1H, br s), 1.66 (3H, s), 1.55 (3H, d, J=6.8 Hz). LCMS (Method K): RT=3.01 min, [M+H]+=389
Reaction SMILES: Br[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5]([O:13][CH3:14])[CH:4]=1.COC1C=CC2N=CC=C([C@@H](O)[C@H]3N4C[C@H](C=C)[C@@H](CC4)C3)C=2C=1.C(OC(C)C)(C)C>C(#N)C>[CH3:14][O:13][C:5]1[CH:4]=[C:3]([CH3:2])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1
Reactant: COc1cc(CBr)c2ccccc2n1
Agent: C=C[C@H]1CN2CC[C@H]1C[C@H]2[C@H](O)c1ccnc2ccc(OC)cc12
Solvent: CC(C)OC(C)C
Solvent: CC#N
Product: COc1cc(C)c2ccccc2n1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
The 4-(bromomethyl)-2-methoxyquinoline obtained in Step 2 was dissolved in 7 mL of acetonitrile, and then 0.5 g (1.54 mmol) of quinine was added, and stirred for 2 hours while heated at 70° C. After stirring was completed, the solution was cooled to a normal temperature, and 20 mL of diisopropyl ether was added. Then, the solution was filtered under reduced pressure to separate a solid precipitated in the reaction solution. The resultant residual solid was washed with a mixed solvent of 5 mL of chloroform and 15 mL of diisopropyl ether. After washing, the solid was dried under reduced pressure to obtain 0.82 g of the target compound, 2-methoxy-4-methyl quinoline quininium bromide. The melting point was 181° C. to 191° C. (degradation). M+496 was confirmed by LCMS.
Reaction SMILES: [F:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[Cl:15]C1C(C(F)(F)F)=CC=CC=1C(O)=O>>[F:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:15])=[O:5]
Reactant: O=C(O)c1cccc(C(F)(F)F)c1F
Reactant: O=C(O)c1cccc(C(F)(F)F)c1Cl
Product: O=C(Cl)c1cccc(C(F)(F)F)c1F

Procedure:
Intermediate 13 was prepared in a similar manner as Intermediate 12 substituting 2-fluoro-3-(trifluoromethyl)benzoic acid for 2-chloro-3-(trifluoromethyl)benzoic acid.
Reaction SMILES: [CH2:1]([C:8]1[C:9]([NH:21][CH:22]([CH2:26][CH2:27][CH2:28][CH3:29])[C:23](O)=[O:24])=[N:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[CH2:1]([C:8]1[NH:13][C:12]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[CH:11][N:10]2[C:23](=[O:24])[C:22]([CH2:26][CH2:27][CH2:28][CH3:29])=[N:21][C:9]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCC(Nc1ncc(-c2ccc(O)cc2)nc1Cc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCc1nc2c(Cc3ccccc3)[nH]c(-c3ccc(O)cc3)cn-2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.3 %

Procedure:
2-((3-benzyl-5-(4-hydroxyphenyl)pyrazin-2-yl)amino)hexanoic acid (130 mg, 0.33 mmol) was dissolved in DCM (10 mL). Pyridine (0.5 mL) was added followed by N,N′-Dicyclohexylcarbodiimide (137 mg, 0.67 mmol). The reaction mixture was slowly stirred at room temperature for 1 hr. The solvent was evaporated, and the residue purified by flash chromatography (eluting solvent: EtOAc to DCM to 10% methanol in DCM) to give the product as a yellow powder (110 mg, 89%). 1H NMR (300 MHz, CD3OD, δ): 7.30 (m, 8H), 6.88 (d, 2H), 4.40 (s, 2H), 2.84 (t, 2H), 1.77 (m, 2H), 1.51 (m, 2H), 0.89 (m, 3H); MS (ESI) m/z 374.3 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][S:11](Cl)(=[O:13])=[O:12])([O-:3])=[O:2].[NH3:15]>C(OCC)C>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][S:11]([NH2:15])(=[O:13])=[O:12])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1CS(=O)(=O)Cl
Reactant: N
Solvent: CCOCC
Product: NS(=O)(=O)Cc1ccccc1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
To a suspension of 29.4 g of the product of Example 2 in 250 ml of diethyl ether was added 6.5 ml of anhydrous ammonia at 5°-15°. After stirring at 15°-25° for 1 hour, the product was filtered off, washed with ether, and water and oven dried at 60° to give 20.5 g of 2-nitrophenylmethanesulfonamide, m.p.=134°-136°.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[OH:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH:11]3[NH:18][C:19]([C@@H:21]3[CH2:25][C:24]([F:27])([F:26])[CH2:23][NH:22]3)=O)[CH2:9]1)[CH2:15]2>C1COCC1>[F:27][C:24]1([F:26])[CH2:23][NH:22][C@H:21]([CH2:19][NH:18][CH:11]2[CH:12]3[CH2:17][C:8]4([OH:7])[CH2:15][CH:14]([CH2:16][CH:10]2[CH2:9]4)[CH2:13]3)[CH2:25]1
Reactant: O=C(NC1C2CC3CC1CC(O)(C3)C2)[C@@H]1CC(F)(F)CN1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OC12CC3CC(C1)C(NC[C@@H]1CC(F)(F)CN1)C(C3)C2
Yield: 43.7 %

Procedure:
Lithium aluminium hydride (0.51 g) was added in portions to the solution of (S)-4,4-difluoro-pyrrolidine-2-carboxylic acid (5-hydroxy-adamantan-2-yl)-amide (1.2 g) in THF (15 mL) at RT. The reaction mixture was refluxed for 24 h. The reaction mixture was quenched with saturated aqueous sodium sulfate solution (15 mL) at 0° C., filtered through Celite® and extracted with ethyl acetate (3×10 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under high vacuum using rotary evaporator to give a crude material, which was purified through column chromatography (3% MeOH:DCM, silica 100-200 mesh, Diameter of column—2.5 cm, Height of silica—approx. 7 inch) to afford the desired 4-[((S)-4,4-difluoro-pyrrolidin-2-ylmethyl)-amino]-adamantan-1-ol as a white solid (0.5 g).
Reaction SMILES: [C:1]1([CH2:7][S:8]([CH2:11][CH:12]([CH2:16][O:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:13]([OH:15])=O)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:24][CH:25]([CH2:39][CH3:40])[C@@H:26]([C:28]1[N:32]=[C:31]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[O:30][N:29]=1)[OH:27]>>[C:1]1([CH2:7][S:8]([CH2:11][CH:12]([CH2:16][O:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:13]([NH:24][C@H:25]([C:26]([C:28]2[N:32]=[C:31]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[O:30][N:29]=2)=[O:27])[CH2:39][CH3:40])=[O:15])(=[O:9])=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)C(COC1CCOCC1)CS(=O)(=O)Cc1ccccc1
Reactant: CCC(N)[C@H](O)c1noc(-c2ccccc2)n1
Product: CC[C@H](NC(=O)C(COC1CCOCC1)CS(=O)(=O)Cc1ccccc1)C(=O)c1noc(-c2ccccc2)n1

Procedure:
It is similarly prepared according to general procedure given for Example 1 above but using 2-Phenylmethanesulfonylmethyl-3-(tetrahydro-pyran-4-yloxy)-propionic acid and (S)-2-amino-1-(5-phenyl-1,2,4-oxadiazol-3-yl)-butan-1-ol.
Reaction SMILES: [C:1]1([CH2:7][NH:8][CH2:9][C@H:10]2[CH2:14][CH2:13][CH2:12][NH:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Br[CH:23]([CH2:28]Br)[C:24]([O:26][CH3:27])=[O:25]>C1(C)C=CC=CC=1.C(OCC)C.[Cl-].[Na+].O>[CH2:7]([N:8]1[C@H:23]([C:24]([O:26][CH3:27])=[O:25])[CH2:28][N:11]2[CH2:12][CH2:13][CH2:14][C@@H:10]2[CH2:9]1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)C(Br)CBr
Reactant: c1ccc(CNC[C@H]2CCCN2)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1CN2CCC[C@@H]2CN1Cc1ccccc1
Temperature: 90 °C
Yield: 45.9 %

Procedure:
To a suspension of 1-phenyl-N-[(2R)-pyrrolidin-2-ylmethyl]methanamine (13.6 g) in toluene (120 mL) were added triethylamine (22.9 mL) and methyl 2,3-dibromopropanoate (13.4 g) under ice-cooling, and the mixture was stirred with heating at 90° C. for 5 hr. The reaction mixture was allowed to cool to room temperature, and diluted with diethyl ether (200 ml) and brine (200 mL). The organic layer was dried over anhydrous magnesium sulfate, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography (ethyl acetate/hexane=10/80→50/50) to give the title compound (6.86 g) as a pale-yellow oil.
Reaction SMILES: [CH3:1][NH2:2].Br[C:4]1[C:5]([NH2:11])=[N:6][CH:7]=[C:8]([Br:10])[N:9]=1>C(O)C>[NH2:11][C:5]1[C:4]([NH:2][CH3:1])=[N:9][C:8]([Br:10])=[CH:7][N:6]=1
Reactant: CN
Reactant: Nc1ncc(Br)nc1Br
Solvent: CCO
Product: CNc1nc(Br)cnc1N
Temperature: 130 °C
Reaction time: 17 h
Yield: 40 %

Procedure:
1.55 g (50 mmol) of 40% strength aqueous methylamine solution is added to a solution of 2.53 g (10 mmol) of 3,5-dibromo-2-aminopyrazine in ethanol. The mixture is stirred in an autoclave at 130° C. for 17 hours. After evaporation of the solvent under reduced pressure, the product is purified by chromatography on a silica column (eluant=CH2Cl2, to which 3% of CH3OH has been added). 0.8 g (Yld=40%) of 2-amino-5-bromo-3-methylaminopyrazine (m.p. 121° C.) is obtained.
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]([C:7]1[CH:8]=[C:9]2[CH:19]=[CH:18][S:17][C:10]2=[N:11][C:12]=1[C:13]([O:15][CH3:16])=[O:14])=[O:6].C([O-])(=O)C.[Na+]>C(O)(=O)C.O>[Br:1][C:19]1[C:9]2[C:10](=[N:11][C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:7]([C:5]([O:4][CH3:3])=[O:6])[CH:8]=2)[S:17][CH:18]=1
Reactant: COC(=O)c1cc2ccsc2nc1C(=O)OC
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1cc2c(Br)csc2nc1C(=O)OC
Temperature: 75 °C
Reaction time: 6 h

Procedure:
Bromine (0.33, 0.00206 mol) in acetic acid (8 mL) is added to a stirred solution of dimethylthieno[2,3-b]pyridine-5,6-dicarboxylate (0.5 g, 0.00187 mol) in acetic acid containing sodium acetate (0.31 g, 0.00377 mol) at 40° C. The reaction mixture is heated at 75° C. for 18 hours. Evaluation of the mixture by tlc (silica gel) indicated incomplete reaction. Additional bromine (0.33 g) in acetic acid and sodium acetate (0.31 g) is added and heating at 75° C. continued for six hours. The reaction mixture is diluted with water and extracted into ethyl acetate. The separated organic layer is dried over anhydrous MgSO4, filtered, and the filtrate concentrated to an oil which solidifies on standing. Crystallization of the crude product from ethyl acetate-hexanes yields the dimethyl 3-bromothieno[2,3-b]pyridine-5,6-dicarboxylate as white needles mp 86°-87.5° C.
Reaction SMILES: C[Al](C)C.[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([NH2:12])=[N:10][CH:11]=1.[Si:13]([O:20][CH2:21][C@@H:22]([O:24][CH2:25][C@H:26]([O:31][C:32]1[N:37]=[CH:36][N:35]=[C:34]2[N:38]([C:41]3[C:46]([Cl:47])=[CH:45][CH:44]=[CH:43][N:42]=3)[N:39]=[CH:40][C:33]=12)[C:27](OC)=[O:28])[CH3:23])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>C1(C)C=CC=CC=1.CCOC(C)=O>[Si:13]([O:20][CH2:21][C@@H:22]([O:24][CH2:25][C@H:26]([O:31][C:32]1[N:37]=[CH:36][N:35]=[C:34]2[N:38]([C:41]3[C:46]([Cl:47])=[CH:45][CH:44]=[CH:43][N:42]=3)[N:39]=[CH:40][C:33]=12)[C:27]([NH:12][C:9]1[CH:8]=[CH:7][C:6]([Cl:5])=[CH:11][N:10]=1)=[O:28])[CH3:23])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: Nc1ccc(Cl)cn1
Reactant: COC(=O)[C@H](CO[C@@H](C)CO[Si](C)(C)C(C)(C)C)Oc1ncnc2c1cnn2-c1ncccc1Cl
Agent: C[Al](C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C[C@@H](CO[Si](C)(C)C(C)(C)C)OC[C@H](Oc1ncnc2c1cnn2-c1ncccc1Cl)C(=O)Nc1ccc(Cl)cn1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 50.5 %

Procedure:
Trimethylaluminium (2M in hexanes)(0.551 mL, 1.10 mmol) was added to 5-chloropyridin-2-amine (135 mg, 1.05 mmol) in toluene (8 mL) cooled to 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 20 minutes. (2S)-methyl 3-((S)-1-(tert-butyldimethylsilyloxy)propan-2-yloxy)-2-(1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)propanoate (Intermediate AO2) (500 mg, 0.96 mmol) in toluene (8 mL) was added and the reaction was heated to 100° C. for 5 hours in the microwave reactor. The reaction was allowed to cool to room temperature before adding EtOAc (30 mL) and 20% sodium potassium tartrate solution (30 mL), which was stirred vigorously for 16 hours. The phases were separated and the organic layer was washed with sat. brine (15 mL), dried (MgSO4) and evaporated to give crude product (300 mg) that was used without further purification. m/z (ES+), (M+H)+=618.44; HPLC tR=23.55 min
Reaction SMILES: C([Li:5])CCC.C(NC(C)C)(C)C.[CH2:13]([SnH:17]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16]>C1COCC1>[CH2:22]([Sn:17]([Li:5])([CH2:13][CH2:14][CH2:15][CH3:16])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:23][CH2:24][CH3:25]
Reactant: [Li]CCCC
Reactant: CCCC[SnH](CCCC)CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: [Li][Sn](CCCC)(CCCC)CCCC
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
In a Schlenk tube at −10° C., 1.7 ml (2.6 mmol) of butyllithium (1.5M in hexane) are added, dropwise, to a solution of 0.4 ml (2.6 mmol) of freshly distilled diisopropylamine in anhydrous THF (50 ml). After 5 min, 0.70 ml (2.6 mmol) of tributyltin hydride is added. The stirring is maintained for 30 min at 0° C. A pale green solution of tributylstannyllithium is obtained, which solution will be cooled to −78° C. before adding, dropwise, 294.5 μl (2.6 mmol) of 2-bromo-6-methyl-pyridine. The mixture is kept at −78° C. for two hours. After a return to ambient temperature, the solvent is evaporated off under vacuum. The residue is taken up with dichloromethane and then washed with water. The organic phase is dried over MgSO4, and evaporated to dryness. The product is purified by chromatography on an alumina column (eluent: ethyl acetate/petroleum ether=0.5/9.5), the stannylated pyridine 22 being isolated in the form of a yellow oil, with a yield of 82%.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.CS(O)(=O)=O.[Br:17][C:18]1[CH:19]=[C:20]([CH:22]=[C:23]([CH3:25])[CH:24]=1)[NH2:21]>O1CCOCC1>[Br:17][C:18]1[CH:19]=[C:20]([NH:21][C:2]2[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=2)[CH:22]=[C:23]([CH3:25])[CH:24]=1
Reactant: Cc1cc(N)cc(Br)c1
Reactant: FC(F)(F)c1ccnc(Cl)n1
Agent: CS(=O)(=O)O
Solvent: C1COCCO1
Product: Cc1cc(Br)cc(Nc2nccc(C(F)(F)F)n2)c1
Yield: 68.9 %

Procedure:
2-Chloro-4-(trifluoromethyl)pyrimidine (182 g, 995 mmol) and methanesulfonic acid (97.5 g, 1.02 mol) were added sequentially to a solution of 3-bromo-5-methylaniline (162.5 g, 874 mmol) in 1,4-dioxane (2 L). The resulting solution was heated to reflux overnight then cooled and concentrated under reduced pressure. The residue was diluted with water (2 L), adjusted to pH 7-8 with aqueous sodium bicarbonate solution and extracted with EtOAc (2×2 L). The organic layers were combined, washed with water (2×2 L), dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford N-(3-bromo-5-methylphenyl)-4-(trifluoromethyl)pyrimidin-2-amine (200 g, 602 mmol, 69%) as a light yellow solid. MS ESI calcd. For C11H8BrF3N4 [M+H]+ 332, 334.0. found 332, 334. 1H NMR (400 MHz, CDCl3): δ 8.68 (d, J=4.9 Hz, 1H), 7.79 (s, 1H), 7.30 (s, 2H), 7.10-7.06 (m, 2H), 2.36 (s, 3H). Synthetic Reference: PCT Int. Appl., 2011075517; PCT Int. Appl., 2011075515.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[O:30][CH:29]=[N:28][C:27]=2[C:31](O)=[O:32])=[CH:22][CH:21]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:31]([C:27]3[N:28]=[CH:29][O:30][C:26]=3[C:23]3[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=3)=[O:32])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)c1ncoc1-c1ccc(Cl)cc1
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)c3ncoc3-c3ccc(Cl)cc3)cn2)o1

Procedure:
Following general procedure B followed by T, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and 5-(4-chloro-phenyl)-oxazole-4-carboxylic acid. LC-MS-conditions 01b: tR=0.96 min; [M+H]+=411.11.
Reaction SMILES: [OH:1][C:2]([CH2:5][CH2:6][CH2:7][C@H:8]([C@@H:10]1[C@:28]2([CH3:29])[C@H:13]([C@H:14]3[C@H:25]([CH2:26][CH2:27]2)[C@:23]2([CH3:24])[C:17]([CH2:18][C@H:19]([CH2:21][CH2:22]2)[OH:20])=[CH:16][CH2:15]3)[CH2:12][CH2:11]1)[CH3:9])([CH3:4])[CH3:3].[C:30](Cl)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>N1C=CC=CC=1>[C:30]([O:20][C@H:19]1[CH2:21][CH2:22][C@@:23]2([CH3:24])[C:17](=[CH:16][CH2:15][C@@H:14]3[C@@H:25]2[CH2:26][CH2:27][C@@:28]2([CH3:29])[C@H:13]3[CH2:12][CH2:11][C@@H:10]2[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][C:2]([O:1][C:30](=[O:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([CH3:3])[CH3:4])[CH2:18]1)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: C[C@H](CCCC(C)(C)O)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: c1ccncc1
Product: C[C@H](CCCC(C)(C)OC(=O)c1ccccc1)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC(=O)c5ccccc5)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Heat 2.9 gm. (7.2 mmole) of 25-hydroxycholesterol with 2.1 ml. (18 mmole) of benzoyl chloride in 30 ml. of pyridine at 70°-80° C. for 4 hours. Add an additional 1.4 ml. (12 mmole) of benzoyl chloride and continue heating at 75°-80° C. for 1 hour. Pour the reaction mixture into ice-water mixture (b 1:1, 500 gm.) Stir for 1 hour, separate the precipitate and wash with ice-water. Recrystalize from acetone. Dissolve the crude product (3.8 gm.) in methylene chloride-hexane (3:2, 40 ml.) and pass the solution through a silica gel column (120 gm.). Elute the column with 800 ml. methylene chloride-hexane (5:1) followed by 800 ml. methylene chloridehexane (10:1). Combine the fractions and concentrate to a residue. Recrystalize from acetone to obtain the pure product (3.32 gm., m.p. 130°-132° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:22]=[CH:23][C:24]=1[N+:25]([O-])=O)[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH:10]=1)=[O:7].[CH3:28][S:29](Cl)(=[O:31])=[O:30].Cl>CO.[Pd].N1C=CC=CC=1>[CH3:28][S:29]([NH:25][C:24]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH:10]=2)=[O:7])=[CH:4][C:3]=1[O:2][CH3:1])(=[O:31])=[O:30]
Reactant: COc1ccc(NC(=O)c2ccc([N+](=O)[O-])c(OC)c2)cc1NS(C)(=O)=O
Reactant: CS(=O)(=O)Cl
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: COc1ccc(NC(=O)c2ccc(NS(C)(=O)=O)c(OC)c2)cc1NS(C)(=O)=O
Reaction time: 2 h
Yield: 86 %

Procedure:
A suspension of 3-methoxy-4-nitro-N-(3-methanesulfonylamino-4-methoxyphenyl)benzamide (1.4 g) in methanol (20 ml) was stirred under hydrogen with palladium on carbon (10%, 50 mg) for 18 hours. The solvents were removed in vacuo to give a brown gum. The residue was dissolved in pyridine (5 ml) and cooled to 0° C. when methanesulfonyl chloride (0.5 ml) was added, the mixture was kept at 0° C. for a further 2 hours then brought to R.T. for 1 h. The mixture was poured onto ice (50 g) and hydrochloric acid (3M, 50 g), the resultant brown solid filtered and washed with water to give 4-methanesulfonylamino-3-methoxy-N-(3-methanesulfonylamino-4-methoxyphenyl)benzamide (1.26 g, 86%) as a brown solid.
Reaction SMILES: CC[O:3][C:4]([CH:6]1[N:14]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[CH2:7]1)=[O:5].[OH-].[Li+]>C1COCC1.CO.O>[C:18]([O:17][C:15]([N:14]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[CH2:7][CH:6]1[C:4]([OH:5])=[O:3])=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: CCOC(=O)C1Cc2cccnc2N1C(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1c2ncccc2CC1C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.2 %

Procedure:
A suspension of 2,3-dihydro-pyrrolo[2,3-b]pyridine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester (1 g) and lithium hydroxide (0.25 g) in 6 ml THF, 3 ml MeOH and 3 ml water was stirred 0.5 h at rt. The reaction mixture was poured onto 1M HCl/ice and washed three times with dichloromethane. The aqueous layer was neutralized with 1M NaOH, evaporated to dryness and purified by chromatography (silica gel, dichloromethane/methanol, 4/1) to yield 2,3-dihydro-pyrrolo[2,3-b]pyridine-1,2-dicarboxylic acid 1-tert-butyl ester as a white solid (400 mg). MS: 263.4 (M−H)−