Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:3]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[CH:9][CH:8]=1)=[O:4].Cl.[CH3:22][NH:23][CH3:24].C(N(CC)CC)C>C1COCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:13]([C:10]1[CH:11]=[CH:12][C:7]([CH2:6][NH:5][C:3](=[O:4])[CH:2]([N:23]([CH3:24])[CH3:22])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:8][CH:9]=1)#[N:14]
Reactant: N#Cc1ccc(CNC(=O)C(Br)c2ccccc2)cc1
Reactant: CNC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)C(C(=O)NCc1ccc(C#N)cc1)c1ccccc1
Reaction time: 19 h
Yield: 92.6 %

Procedure:
To a stirred solution of (RS)-2-bromo-N-(4-cyano-benzyl)-2-phenyl-acetamide (200 mg) in THF (10 ml) at rt under an Ar atmosphere were added dimethylamine, hydrochloride (149 mg), triethylamine (0.42 ml) and tetrabutylammonium iodide (34 mg). The reaction mixture was stirred for 19 hrs, then treated with additional dimethylamine, hydrochloride (149 mg) and triethylamine (0.42 ml). After another 8 hrs stirring at rt, the solids were filtered off and washed with EtOAc. The filtrate was washed with water and brine, dried over MgSO4 and concentrated. The product was isolated by chromatography (silica gel, gradient dichloromethane=>dichloromethane/MeOH 9:1) to give (RS)-N-(4-cyano-benzyl)-2-dimethylamino-2-phenyl-acetamide (165 mg). Orange solid. MS 294.3 ([M+H]+)
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([C:22](=O)[CH2:23][CH2:24][CH3:25])[C:17](OCC)=[O:18])=[CH:11][CH:10]=1)#[N:2].Cl.[CH3:28][C:29]1[CH:33]=[C:32]([NH:34][CH:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)[NH:31][N:30]=1.C(N(CC)C1C=CC=CC=1)C>C(OCC)(=O)C>[CH3:28][C:29]1[CH:33]=[C:32]2[N:34]([CH:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[C:17](=[O:18])[C:16]([CH2:15][C:12]3[CH:13]=[CH:14][C:9]([C:4]4[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=4)=[CH:10][CH:11]=3)=[C:22]([CH2:23][CH2:24][CH3:25])[N:31]2[N:30]=1
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OCC
Reactant: Cc1cc(NC2CCOCC2)[nH]n1
Agent: Cl
Solvent: CCN(CC)c1ccccc1
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCOCC2)c2cc(C)nn12
Temperature: 180 °C
Reaction time: 2 h
Yield: 42 %

Procedure:
A mixture of ethyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate (0.96 g), 3-methyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-amine hydrochloride (0.3 g) and N,N-diethylaniline (10 mL) was stirred at 180° C. for 2 hr. The obtained reaction mixture was diluted with ethyl acetate, washed 3 times with 1 N hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.27 g, 42%).
Reaction SMILES: Cl[S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[CH2:8]([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[OH:17])[CH3:9]>C1(C)C(C)=CC=CC=1>[CH2:8]([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3])[CH3:9]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CCOc1ccccc1O
Solvent: Cc1ccccc1C
Product: CCOc1ccccc1OS(=O)(=O)N=C=O
Temperature: 140 °C

Procedure:
67.9 g (0.48 mol) of chlorosulfonyl isocyanate are added dropwise at 25° C. to a solution of 55.2 g (0.4 mol) of 2-ethoxyphenol in 500 ml of xylene. When the dropwise addition is complete, the temperature is increased slowly to 140° C. and the mixture is refluxed for 2.5 hours. The mixture is cooled, and the solvent as well as excess chlorosulfonyl isocyanate are removed on a rotary evaporator. The yellow oil which remains (97.2 g=100% of theory) is employed without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[S:10][C:9]3[N:11]=[C:12]([N:19]4[CH2:24][CH2:23][CH:22]([NH:25]C=O)[CH2:21][CH2:20]4)[CH:13]=[C:14]([C:15]([F:18])([F:17])[F:16])[C:8]=3[C:4]=2[N:5]=[CH:6][N:7]=1>Cl.O.C(=O)([O-])[O-].[Na+].[Na+]>[NH2:25][CH:22]1[CH2:23][CH2:24][N:19]([C:12]2[CH:13]=[C:14]([C:15]([F:16])([F:18])[F:17])[C:8]3[C:4]4[N:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]=4[S:10][C:9]=3[N:11]=2)[CH2:20][CH2:21]1
Reactant: Nc1ncnc2c1sc1nc(N3CCC(NC=O)CC3)cc(C(F)(F)F)c12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Nc1ncnc2c1sc1nc(N3CCC(N)CC3)cc(C(F)(F)F)c12
Temperature: 80 °C

Procedure:
The above yellow formamide (268 mg, 0.676 mmol) was dissolved in 3 mL of 6% HCl. This solution was heated at 80° C. for 40 min. The reaction mixture was diluted with water and neutralized with sodium carbonate to pH 10. The resulting solid was collected by filtration and recrystallized from MeOH to give the title compound as a white crystalline product (171 mg, 69%).
Reaction SMILES: S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]([C:48]2[CH:64]=[CH:63][C:51]([O:52][C:53]([C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][N:58]=3)([CH3:56])[CH2:54]O)=[CH:50][CH:49]=2)([CH3:47])[CH:44]([CH3:46])[CH3:45])=[CH:39][CH:38]=1.[BH4-].[Na+]>C(Cl)Cl>[I:36][C:37]1[CH:38]=[CH:39][C:40]([C:43]([C:48]2[CH:49]=[CH:50][C:51]([O:52][C:53]([C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][N:58]=3)([CH3:54])[CH3:56])=[CH:63][CH:64]=2)([CH3:47])[CH:44]([CH3:45])[CH3:46])=[CH:41][CH:42]=1
Reactant: CC(C)C(C)(c1ccc(I)cc1)c1ccc(OC(C)(CO)c2ccccn2)cc1
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [BH4-]
Solvent: ClCCl
Product: CC(C)C(C)(c1ccc(I)cc1)c1ccc(OC(C)(C)c2ccccn2)cc1
Reaction time: 0.08 h

Procedure:
A solution of triflic anhydride (1 equiv.) in DCM is added to a solution of triphenylphosphine oxide (2 equiv) in DCM at 0° C. After precipitation is observed (˜15 min), a solution of 5e (1 equiv) in DCM is added. After 5 min, sodium borohydride (4 equiv.) is added in one portion. After completion of reaction, the reaction mixture is quenched with 2 N HCl, poured into saturated aqueous sodium bicarbonate and extracted three times with EtOAc. The combined organic extracts are washed with water, brine, dried (Na2SO4) and concentrated in vacuo. Purification of the crude residue by flash chromatography on silica gel affords the title compound 5f.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([F:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[Cl:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH2:25][NH:26][CH2:27]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[Cl:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH2:25][N:26]([C:11]1[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5][N:4]3[CH:1]3[CH2:2][CH2:3]3)=[C:9]([F:17])[C:10]=1[F:16])[CH2:27]2
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)c(F)c2c1=O
Reactant: Clc1cccc2c1CNC2
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3Cc4cccc(Cl)c4C3)c(F)c(F)c2c1=O
Yield: 21.1 %

Procedure:
210 mg of 1-cyclopropyl-5,6,7,8-tetrafluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 120 mg of 4-chloroisoindoline, 213 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 64 mg of the target compound.
Reaction SMILES: [C:1](=[O:30])([O:8][CH2:9]/[C:10](/[C:20]1[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=1)=[C:11](/[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)\[CH2:12][OH:13])[O:2][CH2:3][CH2:4][CH2:5][CH2:6][Br:7].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=[O:33]>ClCCl>[Br:7][CH2:6][CH2:5][CH2:4][CH2:3][O:2][C:1]([O:8][CH2:9]/[C:10](/[C:20]1[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:27])=[O:28])=[CH:22][CH:21]=1)=[C:11](/[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)\[C:12]([OH:33])=[O:13])=[O:30]
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Reactant: CS(=O)(=O)c1ccc(/C(COC(=O)OCCCCBr)=C(/CO)c2ccccc2)cc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(/C(COC(=O)OCCCCBr)=C(/C(=O)O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.6 %

Procedure:
A solution of 4.2 g of 4-bromobutyl (2Z)-4-hydroxy-2-[4-(methylsulfonyl)phenyl]-3-phenylbut-2-en-1-yl carbonate in 50 mL of dichloromethane was treated with 4.2 g of Dess-Martin reagent for 1 h at rt. The reaction was quenched by 0.5 mL of water and stirred at rt for 1 h, filtered, and evaporated. The residue was dissolved in a solvent mixture of 30 mL of THF and 30 mL of t-BuOH, and treated with 50 mL of 1 M of H3PO4 and 25 mL of 1 M of NaClO2 in the presence of 5 mL of 2-methyl-2-butene. The resulting mixture was stirred at rt for 15 min; the organic layer was separated, washed with brine, dried (Na2SO4), and evaporated to afford 4 g of the crude acid for further use.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:6]=[CH:7][C:8]=1[F:9].Br[CH2:19][CH2:20][OH:21]>C(O)CCC>[F:17][C:2]([F:16])([F:1])[C:3]1[CH:4]=[C:5]([N:10]2[CH2:11][CH2:12][N:13]([CH2:19][CH2:20][OH:21])[CH2:14][CH2:15]2)[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: OCCBr
Reactant: Fc1ccc(N2CCNCC2)cc1C(F)(F)F
Solvent: CCCCO
Product: OCCN1CCN(c2ccc(F)c(C(F)(F)F)c2)CC1

Procedure:
10 g (0.04 mole) 4-(3-Trifluoromethyl-4-fluorophenyl)piperazine and 7 g (0.056 mole) 2-bromoethanol are heated under reflux for 4 hours in 60 ml n-butanol. The mixture is left to cool, filtered and then recrystallised from ethanol.
Reaction SMILES: CC1C(C(O)=O)=CN=C([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)N=1.N1(N)C2C(=NC=CC=2)C=C1.[F:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[N:33]([NH:37][C:38]([C:40]1[C:41]([CH3:52])=[N:42][C:43](C3C=CC=CN=3)=[N:44][CH:45]=1)=[O:39])[CH:32]=[CH:31]2>>[F:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[N:33]([NH:37][C:38]([C:40]1[C:41]([CH3:52])=[N:42][C:43]([C:16]3[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=3)=[N:44][CH:45]=1)=[O:39])[CH:32]=[CH:31]2
Reactant: Cc1nc(-c2ccccn2)ncc1C(=O)O
Reactant: Cc1nc(-c2ccccn2)ncc1C(=O)Nn1ccc2cc(F)ccc21
Agent: Nn1ccc2ncccc21
Product: Cc1nc(-c2cccnc2)ncc1C(=O)Nn1ccc2cc(F)ccc21

Procedure:
Following procedures similar to those of Example 127 but substituting 4-methyl-2-pyridin-3-yl-pyrimidine-5-carboxylic acid for 4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid, and substituting 5-fluoro-indol-1-ylamine for pyrrolo[3,2-b]pyridine-1-ylamine, there is prepared 4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid (5-fluoro-indol-1-yl)-amide (34%) as a solid. MS: 348 (M+H); 1H NMR (300 MHz, CD3OD): δ 2.85 (s, 3H), 6.57 (m, H), 7.02 (m, H), 7.23-7.46 (m, 2H), 7.62 (m, H), 8.70 (d, H), 8.91 (d, H), 9.17 (s, H), 9.63 (s, H).
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[CH:16]([CH2:17][C:18](=[O:28])[CH2:19][CH2:20]2)[C:15](=[O:29])C=3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].[OH2:30].O.O.O.O.O.O.[Cl-].[Ce+3].[Cl-].[Cl-].[BH4-].[Na+].[Cl-].[NH4+]>CO>[OH:28][C@@H:18]1[CH:19]=[CH:20][C@@:21]2([CH3:22])[C@@H:16]([C:15](=[O:30])[O:29][C:13]3[C@H:12]4[C@:26]([CH3:27])([CH2:25][CH2:24][C:23]=32)[C@@H:9]([C@H:7]([CH3:8])[CH2:6][CH2:5][CH2:4][CH:2]([CH3:1])[CH3:3])[CH2:10][CH2:11]4)[CH2:17]1
Reactant: CC(C)CCC[C@H](C)[C@H]1CC[C@H]2C3=CC(=O)C4CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: O
Agent: [BH4-]
Agent: [Ce+3]
Agent: [Cl-]
Solvent: CO
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2C3=C(CC[C@]12C)[C@@]1(C)C=C[C@@H](O)C[C@@H]1C(=O)O3
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 88.4 %

Procedure:
Compound 4 (19 mg, 0.048 mmol) obtained in Example 4 was suspended in methanol (1.0 mL), and cerium chloride heptahydrate (36 mg, 0.096 mmol) and sodium borohydride (0.9 mg, 0.024 mmol) were added thereof at 0° C., followed by stirring at room temperature for 10 minutes. A saturated aqueous ammonium chloride solution was added to the reaction mixture, followed by extraction with ethyl acetate twice. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to yield a residue. The residue was purified by preparative thin layer chromatography to obtain the title compound (17 mg, 91%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]([C:16]1[N:17]=[CH:18][N:19](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:20]=1)([OH:15])[CH3:14])[CH:7]=[CH:6]2.Cl>C(O)=O>[NH:19]1[CH:20]=[C:16]([C:13]([C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:9]=2)([OH:15])[CH3:14])[N:17]=[CH:18]1
Reactant: COc1ccc2cc(C(C)(O)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc2c1
Agent: Cl
Solvent: O=CO
Product: COc1ccc2cc(C(C)(O)c3c[nH]cn3)ccc2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 90.8 %

Procedure:
1-(6-Methoxynaphthalen-2-yl)-1-(1-trityl-1H-imidazol-4-yl)ethanol (2.20 g) was dissolved in 90% formic acid (15 ml), and the solution was stirred at room temperature for 15 h. To the solution was added 1 N-hydrochloric acid, and precipitate was filtered off. The filtrate was neutralized with potassium carbonate, and extracted with ethyl acetate. The extract was washed with saturated aqueous solution of sodium chloride, dried and concentrated. The residue was purified by silica gel column chromatography (eluent, ethyl acetate:methanol=20:1 chloroform:methanol=10:1) to give the titled compound (1.05 g) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[C:6]([I:9])[CH:5]=[C:4]([CH:10]([OH:12])[CH3:11])[N:3]=1.[H-].[Na+].Cl[CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19].[I-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([O:8][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])=[C:6]([I:9])[CH:5]=[C:4]([CH:10]([OH:12])[CH3:11])[N:3]=1
Reactant: CC(O)c1cc(I)c(O)c(Cl)n1
Reactant: CC(C)=CCCl
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)=CCOc1c(I)cc(C(C)O)nc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
2-Chloro-3-hydroxy-6-(1-hydroxyethyl)-4-iodo-pyridine (2.99 g, 10 mmole) was dissolved in 15 ml dry dimethylformamide in an oven dried 100 ml two neck round bottom flask under nitrogen. The solution was cooled to 0° C., was treated with sodium hydride (400 mg, 10 mmole), and the mixture was stirred 1 h at room temperature. The mixture was treated with 1-chloro-3-methyl-2-butene (1.2 ml, 11 mmole) and sodium iodide (150 mg, 1 mmole) and the reaction mixture was stirred 18 h at room temperature. The reaction mixture was diluted with 100 ml ethyl acetate, was washed with 4×50 ml 50% saturated 1:1 sodium chloride/sodium bicarbonate, and was dried over anhydrous potassium carbonate. The dried organics were concentrated in vacuo to a yellow oil which was crystallized from 25 ml hexane to give 3.2 g (87%) of 2-chloro-3-(3-methyl-2-butenyloxy)-6-(1-hydroxyethyl)-4-iodo-pyridine as an off-white solid, Melting Point: 80-81° C.
Reaction SMILES: [CH:1]1([N:6]2[C:11]3=[N:12][C:13](S(C)=O)=[N:14][CH:15]=[C:10]3[CH2:9][NH:8][C:7]2=[O:19])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]2)=[CH:23][CH:22]=1.FC(F)(F)C(O)=O>C(#N)C.C(OCC)(=O)C>[CH:1]1([N:6]2[C:11]3=[N:12][C:13]([NH:20][C:21]4[CH:22]=[CH:23][C:24]([N:27]5[CH2:28][CH2:29][N:30]([CH3:33])[CH2:31][CH2:32]5)=[CH:25][CH:26]=4)=[N:14][CH:15]=[C:10]3[CH2:9][NH:8][C:7]2=[O:19])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CS(=O)c1ncc2c(n1)N(C1CCCC1)C(=O)NC2
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CN1CCN(c2ccc(Nc3ncc4c(n3)N(C3CCCC3)C(=O)NC4)cc2)CC1
Temperature: 85 °C
Reaction time: 2 h
Yield: 79.5 %

Procedure:
To a solution of 2.0 g (7.1 mmol) of 1-cyclopentyl-7-methanesulfinyl-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one and 2.7 g (14.3 mmol) of 1-(4-aminophenyl)-4-methylpiperazine in 32 mL of acetonitrile is added 2.75 mL (35.7 mmol) of trifluoroacetic acid. The mixture is heated at 85° C. overnight. The cooled reaction mixture is diluted with ethyl acetate and washed two times with saturated aqueous sodium bicarbonate solution and once with brine. The combined aqueous phase is back extracted with dichloromethane. The combined organic phase is dried over magnesium sulfate and concentrated. The dark solid residue is stirred for 2 hours in 30 mL of 1:1 dichloromethane/ethyl acetate, filtered, washed with ethyl acetate, and dried to give 2.3 g (80%) of the title compound: mp 236-239° C. (dec).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[NH2:12][CH2:13][CH:14]([CH3:19])[C:15]([O:17][CH3:18])=[O:16].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([NH:12][CH2:13][CH:14]([CH3:19])[C:15]([O:17][CH3:18])=[O:16])[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Reactant: COC(=O)C(C)CN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C(C)CNc1cc(Br)ccc1[N+](=O)[O-]
Yield: 59.1 %

Procedure:
To a solution of 4-bromo-2-fluoro-1-nitrobenzene (9.4 g, 42.7 mmol) in tetrahydrofuran (100 mL) were added methyl 3-amino-2-methylpropanoate (5 g, 42.7 mmol) and potassium carbonate (11.8 g, 85.4 mmol). The reaction mixture was stirred with refluxing for 3 hours. The mixture was diluted with water (100 mL), extracted with ethyl acetate (100 mL×3). The organic layers were separated, combined, dried over anhydrous sodium sulfate, filtered and concentrated to give a residue, which was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=5:1) to give methyl 3-(5-bromo-2-nitrophenylamino)-2-methylpropanoate as a light yellow solid (8 g, 59%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH2:7]/[C:8](=[CH:12]\[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:17]([CH3:27])[CH:16]=1)/[C:9]([OH:11])=[O:10])([CH3:4])([CH3:3])[CH3:2]>CO>[C:1]([O:5][C:6](=[O:28])[CH2:7][C@@H:8]([CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[C:17]([CH3:27])[CH:16]=1)[C:9]([OH:11])=[O:10])([CH3:3])([CH3:4])[CH3:2]
Reactant: Cc1cc(CC/C=C(\CC(=O)OC(C)(C)C)C(=O)O)ccc1-c1ccccc1
Solvent: CO
Product: Cc1cc(CCC[C@H](CC(=O)OC(C)(C)C)C(=O)O)ccc1-c1ccccc1
Yield: 99.3 %

Procedure:
A solution of (E)-2-[2-(tert-butoxy)-2-oxoethyl]-5-(2-methyl-1,1′-biphenyl-4-yl)-2-pentenoic acid (3.8 g, 10 mmol) and 1,1′-bis[(2S,4S)-2,4-diethylphosphetano]ferrocene-(1,5-cyclooctadiene)-rhodium (I) tetrafluoroborate (7.8 mg, 10 μmol) in methanol (10 ml) was stirred at 20-25° C. for 24 hours, under hydrogen (60 p.s.i.). The mixture was then concentrated in vacuo to leave the title compound as a yellow oil (3.8 g, 98% conversion, enantiomeric excess=95%, 95% pure by NMR).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22]([S:25][CH3:26])=[CH:21][C:20]=1[C:27]([CH3:32])([CH3:31])[CH2:28][CH2:29][OH:30])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>ClCCl>[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22]([S:25][CH3:26])=[CH:21][C:20]=1[C:27]([CH3:32])([CH3:31])[CH2:28][CH:29]=[O:30])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CSc1ccc(OCc2ccccc2)c(C(C)(C)CCO)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CS(C)=O
Solvent: ClCCl
Product: CSc1ccc(OCc2ccccc2)c(C(C)(C)CC=O)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 78.6 %

Procedure:
To a solution of 1.57 mL of oxalyl chloride in 15 mL of dichloromethane at −60° C. was added a solution of 2.55 mL of DMSO in 5 mL of dichloromethane. After 10 minutes, a solution of 3-(2-benzyloxy-5-methylsulfanylphenyl)-3-methylbutan-1-ol (2.84 g, 8.9 mmol) in 5 mL of dichloromethane was added (solids quickly precipitated), followed 15 minutes later by 7.5 mL triethylamine and the reaction mixture became very thick with solids. The reaction mixture was then warmed to room temperature and monitored by TLC. After 1 hour, TLC of an aliquot showed reaction was complete, so water was added to the reaction mixture and the resulting layers were separated. The aqueous layer was washed with dichloromethane and the organics were combined, washed four times with water, washed with brine, dried over magnesium sulfate, and concentrated in vacuo to afford a yellow oil. The residue was purified on SiO2 (0% to 10% ethyl acetate-hexanes) to give 2.2 g (78.7% yield) of 3-(2-benzyloxy-5-methylsulfanylphenyl)-3-methylbutyraldehyde as a colorless oil that slowly crystallized upon standing.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH3:11])=[O:10])=[CH:4][CH:3]=1.[NH:12]1[CH2:15][CH2:14][CH2:13]1>>[N:12]1([S:9]([CH3:11])(=[O:10])=[N:8][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)[CH2:15][CH2:14][CH2:13]1
Reactant: C1CNC1
Reactant: CS(=O)Nc1ccc(Br)cc1
Product: CS(=O)(=Nc1ccc(Br)cc1)N1CCC1

Procedure:
The title compound is prepared from N-(4-bromophenyl)methanesulfinamide and azetidine following a procedure analogous to that described for Intermediate 3 (Step 2). LC (method 1): tR=0.92 min; Mass spectrum (ESI+): m/z=289, 291 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([Cl:12])=[CH:5]2.[C:13]([Si:15]([CH3:18])([CH3:17])[CH3:16])#[CH:14].C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.C(OCC)(=O)C.[Cu](I)I.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:12][C:6]1[N:7]=[CH:8][C:9]2[C:4]([CH:5]=1)=[CH:3][C:2]([C:14]#[C:13][Si:15]([CH3:18])([CH3:17])[CH3:16])=[CH:11][CH:10]=2
Reactant: C#C[Si](C)(C)C
Reactant: Clc1cc2cc(Br)ccc2cn1
Agent: I[Cu]I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccc2cnc(Cl)cc2c1
Temperature: 65 °C
Yield: 69.3 %

Procedure:
A suspension of 6-bromo-3-chloroisoquinoline (240 mg, 1 mmol), ethynyltrimethylsilane (150 mg, 1.5 mmol), triethylamine (150 mg, 1.5 mmol), copper iodide (20 mg, 0.1 mmol), triphenylphosphine (26 mg, 0.1 mmol), and palladium acetate (22.4 mg, 1 mmol) in dry DMF (1 mL) was heated at 65° C. for 30 minutes. The reaction was cooled to room temperature and diluted with ethyl acetate (20 mL). The organic solution was washed with water (20 mL), brine (20 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 20% ethyl acetate in hexane to afford the title compound as a white powder (180 mg, 70%).
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][C:4]=1[O:10][CH2:11][CH:12]1[CH2:14][C:13]1([Cl:16])[Cl:15].C[O-].[Na+].[Cl:20][C:21](OC(Cl)(Cl)Cl)=[O:22]>O.C(Cl)(Cl)Cl.CO>[Cl:20][C:21]([O:9][C:6]1[CH:7]=[CH:8][C:3]([Cl:2])=[C:4]([O:10][CH2:11][CH:12]2[CH2:14][C:13]2([Cl:15])[Cl:16])[CH:5]=1)=[O:22]
Reactant: Oc1ccc(Cl)c(OCC2CC2(Cl)Cl)c1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=C(Cl)Oc1ccc(Cl)c(OCC2CC2(Cl)Cl)c1

Procedure:
The sodium salt of 4-chloro-3-[(2,2-dichlorocyclopropyl)methoxy]phenol as prepared from 20 g of 4-chloro-3-[(2,2-dichlorocyclopropyl)methoxy]phenol and 16 g of a 28% methanol solution of sodium methylate was dissolved in 300 ml of water and the solution was added dropwise to a solution of 5 ml of trichloromethyl chloroformate in 100 ml of chloroform while maintaining the reaction temperature at 10° C. or below. The reaction mixture was allowed to stand for phase separation. The chloroform layer was dried over anhydrous magnesium sulfate and the solvent was then distilled off. There was obtained 22.5 g of 4-chloro-3-[(2,2-dichlorocyclopropyl)methoxy]phenyl chloroformate.
Reaction SMILES: NC1[S:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]([O:13]C)=[O:12])=[C:7]([CH3:15])[C:5]=2[N:6]=1.[OH-].[K+].Cl.[N:19]([O-])=O.[Na+]>>[CH3:15][C:7]1[C:5]2[N:6]=[N:19][S:3][C:4]=2[CH:10]=[CH:9][C:8]=1[C:11]([OH:13])=[O:12]
Reactant: COC(=O)c1ccc2sc(N)nc2c1C
Reactant: O=N[O-]
Agent: Cl
Agent: [K+]
Agent: [Na+]
Product: Cc1c(C(=O)O)ccc2snnc12

Procedure:
5 g of methyl 2-amino-4-methylbenzothiazole-5-carboxylate (0.02 mol) in 28.6 g of 50% strength KOH were stirred at 120° C. for 4 h. The mixture was then neutralized with 10% strength HCl and admixed with an excess of 40% strength NaNO2 solution at 0-10° C. The reaction mixture was acidified and extracted with ethyl acetate. The extract was washed and dried, and the product was obtained by stripping off the solvent. Yield: 1.3 g (28%).